Updated on 2025/06/27

Information

 

写真a

 
IWAMOTO CHIKA
 
Organization
Faculty of Medical Sciences Department of Clinical Medicine Assistant Professor
School of Medicine Department of Medicine(Concurrent)
Title
Assistant Professor
Profile
自身の研究プロジェクトや分担の研究プロジェクトの遂行、医学研究院医学専攻博士過程の大学院生の研究指導も行っている。 非常勤講師として外部研究施設での実験指導も行っている。
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Degree

  • PhD

Research Interests・Research Keywords

  • Research theme: The potential role of genetic mutations iniImmune cells in pancreatic cancer

    Keyword: PDAC, microenvironment, mutation

    Research period: 2024.4 - 2027.3

  • Research theme: Elucidation of the mechanism of macrophage immune checkpoint in pancreatic cancer

    Keyword: pancreatic cancer, macrophage, microenvironment

    Research period: 2021.4 - 2024.3

Awards

  • American Pancreatic Association Poster of Distinction

    2023.11   APA  

  • American Pancreatic Association Poster of Distinction

    2019.8   APA  

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    Background: The tumor microenvironment is diverse depending on the carcinoma. In gastric cancer, it has been reported that bone marrow (BM)-derived cells invade tumor tissues by local inflammatory reaction, form inflammatory microenvironment and produce cytokines and growth factors, leading to promoting carcinogenesis. In pancreatic cancer, mesenchymal stem cells-derived tumor stroma seems to promote tumor development. However, involvement of BM-derived cells on tumor progression and its mechanism remains unclear. We aimed to investigate its involvement in the remodeling of microenvironment and pancreatic cancer progression.
    Methods & Results: Mouse models of allogeneic BM transplantation using newborn KC/ KPC mice were established. KC recipients’ pancreas didn’t turn cancerous, but BM-derived GFP+ cells were engrafted around acinar cells with atrophy. In KPC recipients’ pancreas, BM-derived multilineage hematopoietic cells were accumulated at invasive front, and especially the localization of macrophages including TAM or aSMA+ cells were similar to GFP+ cells. Then, human pancreatic cancer cells (PCCs) co-injected with peripheral blood (PB)-derived macrophages grew invasively in xenotransplantation models. PB-derived macrophages destructed basement membrane than pancreatic stellate cells (PSCs). We investigated the involvement of PB-derived macrophages in the invasive capability of PCCs, and found that the specific subpopulation of those cells led the invasion of PCCs similar to PSCs known as a leading cell in the invasion. Some PB-derived macrophages treated with PCCs supernatant expressed PSC marker.
    Conclusion: The present data suggest that BM-derived cells recruited to pancreas in the pancreatic carcinogenesis are involved in invasion of PCCs, and also that the specific subpopulation of BM-derived macrophages transformed into PSC-like cells and acted as leading cells in the invasion of pancreatic cancer.

  • American Pancreatic Association Young Investigator Travel Award

    2019.8   APA  

  • 膵臓病研究奨励賞

    2018.12   日本膵臓病研究財団  

  • Scientific Accomplishment As An Early Career Investigator

    2018.6   DDW  

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    Introduction: Cancer malignancy increase due to tumor-stroma interactions, whereas cytokines secreted by cancer cells differentiate activated macrophages into tumor associated macrophages (TMAs), which produce angiogenesis factor and cell growth factor to form the tumor microenvironment. In breast cancer, stromal cells, which support cancer cell proliferation and lead cancer cell invasion, were reported to be descended from bone marrow (BM)-derived mesenchymal stem cells. Although BM-derived cells seem to be involved in remodeling of microenvironment and tumor progression in pancreatic cancer, this mechanism remains incompletely understood. We aimed to investigate an association between pancreatic cancer progression and BM-derived cells using KPC mice.
    Methods: To develop the allogeneic BM transplantation models in KPC mice, BM-derived GFP+ cells were intravenously transplanted into KPC mice following sublethal irradiation. The phenotypical characterization of engrafted GFP+ cells was analyzed by flow cytometry (FCM). Derivation of stromal cells associated with tumor-stroma interactions and distribution of TAMs constituting the tumor microenvironment were examined using immunohistochemical staining. To evaluate invasive capacity and proliferation activity of pancreatic cancer cells (PCCs) co-cultured with BM-derived cells, we performed cell invasion assay and cell viability assay.
    Results: The engraftment of BM-derived GFP+ cells was detected in recipients’ peripheral blood, BM, pancreas, liver, and ascites by FCM. The engrafted GFP+ cells expressed CD45 consisting of a few CD4+/ CD8+ T cells, a few NK cells, or macrophages. The efficiency of macrophages engraftment in recipient KPC mice was higher than that of the control. In recipients’ pancreas, GFP+ cells, F4/80+ macrophages, and CD163+ TAMs were accumulated around ADM, PanIN, stroma cells, and at invasive front. None of BM-derived macrophages and TAMs inhabited around normal acinar cells. Invasive capacity of cancer cells co-cultured with BM-derived macrophages significantly increased compared to the control (p<0.05). Distribution of BM-derived GFP+ cells tends to be similar to that of aSMA+ cells, and a few GFP+aSMA+ cells were detected.
    Conclusion: BM-derived lymphocytes, macrophages, and TAMs were engrafted in recipients’ pancreas, and their distribution was biased. The present data suggest that BM-derived cells are involved in the tumor microenvironment constitution and infiltration of PCCs.

  • American Society of Hematology Abstract Achievement Award

    2011.10   アメリカ血液学会  

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Papers

  • Claudin18.2-positive gastric cancer-specific changes in neoadjuvant chemotherapy-driven immunosuppressive tumor microenvironment

    Tsutsumi, C; Ohuchida, K; Yamada, Y; Shimada, Y; Imamura, M; Son, K; Mochida, Y; Katayama, N; Iwamoto, C; Torata, N; Horioka, K; Shindo, K; Mizuuchi, Y; Ikenaga, N; Nakata, K; Onishi, H; Oda, Y; Nakamura, M

    BRITISH JOURNAL OF CANCER   132 ( 9 )   793 - 804   2025.5   ISSN:0007-0920 eISSN:1532-1827

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    Language:English   Publisher:British Journal of Cancer  

    Background: Claudin 18 isoform 2 (CLDN18.2) is a potential therapeutic target in gastric cancer (GC). However, combining chemotherapy with anti-CLDN18.2 antibodies has shown limited efficacy in CLDN18.2-positive GC, and chemotherapy-induced changes in the tumor microenvironment (TME) remain unclear. Methods: This study analyzed 37 GC samples, including 11 CLDN18.2-positive cases, using single-cell RNA sequencing and multiplex immunofluorescence to assess chemotherapy-driven TME changes in CLDN18.2-positive GC. Results: In chemotherapy-treated CLDN18.2-positive GC, cytotoxic natural killer (NK) cells displayed antibody-dependent cytotoxicity (ADCC)-related genes at lower levels than in untreated CLDN18.2-positive GC, while regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) showed TGFB1 expression at higher levels. Additionally, NK cells, Tregs, and TAMs were more abundant in chemotherapy-treated than untreated CLDN18.2-positive GC. These chemotherapy-induced changes were absent in CLDN18.2-negative GC. Cell-cell interaction analysis identified unique interactions in chemotherapy-treated CLDN18.2-positive GC, including CCL5-CCR5 signaling between cytotoxic NK cells (Sender) and effector Tregs (Receptor) and TGFB1-TGFBR signaling between effector Tregs (Sender) and TAMs (Receptor). Cytotoxic NK cells expressed CCL5 at higher levels, CCR5-positive Tregs were more prevalent, and TAMs exhibited higher TGF-β receptor signature scores in chemotherapy-treated than untreated CLDN18.2-positive GC. Conclusions: Our findings indicate that chemotherapy can drive immunosuppressive TME modifications specific to CLDN18.2-positive GC.

    DOI: 10.1038/s41416-025-02981-y

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  • Prognostic nutrition index reveals LAG3 in cytotoxic CD8+T cells and MHC class II in gastric cancer cells

    Tsutsumi, C; Ohuchida, K; Imamura, M; Tan, BY; Shimada, Y; Son, K; Kosai, T; Katayama, N; Mochida, Y; Hayashida, S; Iwamoto, C; Torata, N; Horioka, K; Shindo, K; Mizuuchi, Y; Ikenaga, N; Nakata, K; Oda, Y; Nakamura, M

    CANCER IMMUNOLOGY IMMUNOTHERAPY   74 ( 6 )   176   2025.4   ISSN:0340-7004 eISSN:1432-0851

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    Language:English   Publisher:Cancer Immunology Immunotherapy  

    Background: The prognostic nutrition index (PNI) has recently been highlighted as a predictor of immune checkpoint (IC) inhibitor efficacy in gastric cancer (GC). Although LAG3, an IC molecule, has gained considerable attention, its association with PNI remains unexplored. Materials and methods: We retrospectively analyzed clinical data from 796 GC patients who underwent radical gastrectomy to identify which previously reported nutritional index had the greatest impact on prognosis. Single-cell RNA sequencing was performed on 38 GC tissues, and multiplex immunofluorescence staining was conducted on 59 GC tissues to evaluate the relationship between nutritional indices and IC molecule expression in cytotoxic CD8-positive T cells. Results: A low preoperative PNI was identified as the strongest predictor of poor prognosis among the nutritional indices in GC patients. The expression of not only PDCD1 (encoding PD1) but also LAG3 in cytotoxic CD8-positive T cells was significantly higher in GC with low PNI compared to those with high PNI. Among cytotoxic CD8-positive T cells, the proportion of LAG3-positive cells was greater than that of PDCD1-positive cells, particularly in GC with low PNI, and most LAG3-positive cells did not co-express PDCD1. Additionally, the expression of MHC class II, a ligand for LAG3, was higher in GC cells with high levels of epithelial–mesenchymal transition-related molecules in GC with low PNI compared to those with high PNI. Conclusions: PNI can reflect LAG3 expression in cytotoxic CD8-positive T cells and MHC class II expression in GC cells.

    DOI: 10.1007/s00262-025-04037-9

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  • Neoantigen peptide-pulsed dendritic cell vaccine therapy after surgical treatment of pancreatic cancer: a retrospective study

    Oyama, K; Nakata, K; Abe, T; Hirotaka, K; Fujimori, N; Kiyotani, K; Iwamoto, C; Ikenaga, N; Morisaki, S; Umebayashi, M; Tanaka, H; Koya, N; Nakagawa, S; Tsujimura, K; Yoshimura, S; Onishi, H; Nakamura, Y; Nakamura, M; Morisaki, T

    FRONTIERS IN IMMUNOLOGY   16   1571182   2025.4   ISSN:1664-3224

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    Language:English   Publisher:Frontiers in Immunology  

    Introduction: Pancreatic cancer shows very poor prognosis and high resistance to conventional standard chemotherapy and immunotherapy; therefore, the development of new breakthrough therapies is highly desirable. Method: We retrospectively evaluated the safety and efficacy of neoantigen peptide-pulsed dendritic cell (Neo-P DC) vaccine therapy after surgical treatment of pancreatic cancer. Result: The result showed induction of neoantigen-specific T cells in 13 (81.3%) of the 16 patients who received Neo-P DC vaccines. In survival analysis of the nine patients who received Neo-P DC vaccines after recurrence, longer overall survival was observed in patients with neoantigen-specific T cell induction than those without T cell induction. Notably, only one of the seven patients who received Neo-P DC vaccines as adjuvant setting developed recurrence, and no patient died during median follow-up 61 months after surgery (range, 25-70 months). Furthermore, TCR repertoire analyses were performed in a case treated with Neo-P DC vaccine combined with long and short peptides, and one significantly dominant clone induced by the long peptide was detected among CD4<sup>+</sup> T cell populations. Discussion: The present study suggests the feasibility and efficacy of Neo-P DC vaccine therapy after surgical treatment of pancreatic cancer in both postoperative recurrence cases and adjuvant setting. A case analysis suggests the importance of combination with long peptides targeting CD4<sup>+</sup> T cell.

    DOI: 10.3389/fimmu.2025.1571182

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  • 不活性化CD8+T細胞の腫瘍への浸潤は胃癌において不良予後と関連した(Tumor infiltration of inactive CD8+ T cells was associated with poor prognosis in Gastric Cancer)

    Katayama Naoki, Ohuchida Kenoki, Son Kiwa, Tsutsumi Chikanori, Mochida Yuki, Noguchi Shoko, Iwamoto Chika, Torata Nobuhiro, Horioka Kohei, Shindo Koji, Mizuuchi Yusuke, Ikenaga Naoki, Nakata Kohei, Oda Yoshinao, Nakamura Masafumi

    Gastric Cancer   28 ( 2 )   211 - 227   2025.3   ISSN:1436-3291

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    Language:English   Publisher:シュプリンガー・ジャパン(株)  

    胃癌(GC)は、その複雑な腫瘍免疫微小環境(TIME)のため、免疫チェックポイント阻害薬の効果が限定的である。本研究では、GCの複雑なTIMEにおける様々な免疫細胞の機能について検討した。GC組織におけるCD8+T細胞浸潤を免疫組織化学的に評価し、34例の胃癌患者の腫瘍および正常組織のシングルセルRNAシークエンス解析(scRNA-seq)を行った。CD8+T細胞の浸潤程度により、157例のGC患者をLOW、MID、HIGHに分類した。MID群と比較して、HIGH群およびLOW群の全生存率は明らかに低かった。scRNA-seq解析の結果、HIGH群におけるCD8+T細胞の活性マーカー発現は正常組織よりも低かったが、T細胞誘導ケモカインCCL5の発現は高かった。HIGH群のCD8+T細胞はPD1発現が低く、CTLA4発現が高かった。Epstein-Barrウイルス陰性例のみを対象としたTCRレパートリー解析の結果、CD8+T細胞のクローン性はHIGH群でMID群よりも低かった。さらに、HIGH群では1型従来型樹状細胞の抗原提示能が低く、骨髄細胞由来の抑制性細胞の免疫抑制能が高く、制御性T細胞におけるCTLA4の発現が高かった。以上より、HIGH群ではクローン性の低い不活化CD8+T細胞の浸潤がケモタキシスにより誘導され、GC患者の予後の悪さに結びついていると考えられた。

  • Tumor infiltration of inactive CD8+T cells was associated with poor prognosis in Gastric Cancer

    Katayama, N; Ohuchida, K; Son, K; Tsutsumi, C; Mochida, Y; Noguchi, S; Iwamoto, C; Torata, N; Horioka, K; Shindo, K; Mizuuchi, Y; Ikenaga, N; Nakata, K; Oda, Y; Nakamura, M

    GASTRIC CANCER   28 ( 2 )   211 - 227   2025.3   ISSN:1436-3291 eISSN:1436-3305

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    Language:English   Publisher:Gastric Cancer  

    Background: Gastric cancer (GC) shows limited response to immune checkpoint inhibitors due to its complex tumor immune microenvironment (TIME). This study explores the functions of various immune cells in the complex TIME in GC. Methods: We assessed CD8 + T-cell infiltration of GC tissues by immunohistochemistry, and performed single-cell RNA sequencing (scRNA-seq) of tumor and normal tissues from 34 patients with GC. Results: We categorized 157 GC patients into LOW, MID, and HIGH groups based on their CD8 + T-cell infiltration. Overall survival was notably lower for the HIGH and LOW groups compared with the MID group. Our scRNA-seq data analysis showed that CD8 + T-cell activity markers in the HIGH group were expressed at lower levels than in normal tissue, but the T-cell-attracting chemokine CCL5 was expressed at a higher level. Notably, CD8 + T-cells in the HIGH group displayed lower PD1 expression and higher CTLA4 expression. TCR repertoire analysis using only Epstein–Barr virus-negative cases showed that CD8 + T-cell receptor clonality was lower in the HIGH group than in the MID group. Furthermore, in the HIGH group, the antigen-presenting capacity of type 1 conventional dendritic cells was lower, the immunosuppressive capacity of myeloid-derived suppressor cells was higher, and the expression of CTLA4 in regulatory T-cells was higher. Conclusion: The present data suggest that the infiltration of inactive CD8 + T-cells with low clonality is induced by chemotaxis in the HIGH group, possibly leading to a poor prognosis for patients with GC.

    DOI: 10.1007/s10120-024-01577-4

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  • TIM3 on natural killer cells regulates antibody-dependent cellular cytotoxicity in HER2-positive gastric cancer

    Tsutsumi, C; Ohuchida, K; Tsutsumi, H; Shimada, Y; Yamada, Y; Son, K; Hayashida, S; Katayama, N; Mochida, Y; Iwamoto, C; Torata, N; Horioka, K; Shindo, K; Mizuuchi, Y; Ikenaga, N; Nakata, K; Ota, K; Iwama, E; Yamamoto, M; Tsukamoto, T; Nomura, S; Morisaki, T; Oda, Y; Okamoto, I; Nakamura, M

    CANCER LETTERS   611   217412   2025.2   ISSN:0304-3835 eISSN:1872-7980

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    Language:English   Publisher:Cancer Letters  

    Therapies targeting HER2 are the standard treatment for HER2-positive gastric cancer (GC). Trastuzumab, a monoclonal antibody against HER2, exerts anti-tumor activity through cell growth regulation and antibody-dependent cellular cytotoxicity (ADCC). ADCC is induced by the binding of trastuzumab to Fcγ receptor III (CD16) in natural killer (NK) cells. However, the relationship between immune checkpoint (IC) molecules of NK cells and trastuzumab-induced ADCC is poorly understood. We performed single-cell RNA sequencing (scRNA-seq) and immunohistochemistry to identify IC molecules associated with CD16 expression in NK cells of GC patients. Additionally, we conducted in vitro assays with HER2-transfected GC cells and in vivo experiments using a mouse HER2-positive GC model to assess expression changes in IC molecules in NK cells and their ligands during trastuzumab treatment. In GC patients, the expression of TIM3, an IC molecule, was strongly correlated with that of CD16 in NK cells. In vitro assays showed that ADCC with trastuzumab increased TIM3 expression in NK cells. scRNA-seq analysis revealed that TIM3 expression of cytotoxic NK cells was elevated in HER2-positive GC patients treated with trastuzumab. HMGB1, a TIM3 ligand, was expressed at higher levels in HER2-transfected GC cells than in controls. Furthermore, HMGB1 expression was higher in HER2-positive GC patients treated with trastuzumab compared to untreated HER2-positive GC patients. In the mouse HER2-positive GC model, anti-TIM3 antibodies and trastuzumab demonstrated synergistic anti-tumor effects without toxicity. This study suggests the combined anti-TIM3 antibody and trastuzumab therapy may have potential as a new treatment strategy for HER2-positive GC.

    DOI: 10.1016/j.canlet.2024.217412

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  • Identification of cold tumor induction-related markers in pancreatic cancer and the clinical implication of PCDH7

    Mochida, Y; Ohuchida, K; Zhang, B; Yamada, Y; Tsutsumi, C; Kubo, A; Oyama, K; Shinkawa, T; Iwamoto, C; Torata, N; Abe, T; Ideno, N; Ikenaga, N; Nakata, K; Oda, Y; Nakamura, M

    JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY   151 ( 2 )   45   2025.1   ISSN:0171-5216 eISSN:1432-1335

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    Language:English   Publisher:Journal of Cancer Research and Clinical Oncology  

    Purpose: Pancreatic ductal adenocarcinoma (PDAC) is considered a “cold” tumor because the tumor immune microenvironment (TIME) exhibits poor intratumoral T-cell infiltration. This study aimed to identify the marker genes associated with induction of cold TIME in PDAC cells. Methods: We orthotopically transplanted 10 primary cultures of PDAC derived from KrasG12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) mice into immunocompetent mice and evaluated TIME by immunohistochemistry (IHC) staining of CD8. We divided primary cultures into two groups: cold TIME group with low CD8<sup>+</sup> T-cell infiltration and a hot TIME group with high infiltration. RNA sequencing was performed to identify specific genes in the cold TIME group, and single-cell RNA sequencing (scRNA-seq) data was used for validation. IHC was performed to evaluate expressions in human PDAC samples. Results: We identified six genes specific in PDAC cells to the cold TIME group by RNA sequencing; these were defined as “cold tumor induction–related genes”. Human PDAC scRNA-seq data revealed that cold tumor induction–related genes were significantly and negatively correlated with the number of CD8<sup>+</sup> T-cells (p = 0.0341). These genes included protocadherin 7 (PCDH7). High expression of PCDH7 significantly and negatively correlated with the number of CD8<sup>+</sup> T-cells in scRNA-seq (p = 0.0474) and IHC (p = 0.0110) data using human PDAC samples. PCDH7 was an independent factor for poor prognosis in PDAC (overall survival: hazard ratio = 2.07, p = 0.0367). Conclusion: PCDH7 is a prognostic marker associated with CD8<sup>+</sup> T-cell infiltration for PDAC patients.

    DOI: 10.1007/s00432-025-06095-z

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  • Combination of autophagy inhibition, DC induction, and LAG3 blockade induces potent therapeutic response in PDAC

    Oyama, K; Nakata, K; Ikenaga, N; Tsutsumi, C; Zhang, B; Mochida, Y; Hirotaka, K; Abe, T; Ideno, N; Iwamoto, C; Ohuchida, K; Kuba, K; Nakamura, M

    CANCER SCIENCE   116   959 - 959   2025.1   ISSN:1347-9032 eISSN:1349-7006

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  • Tumor-infiltrating monocytic MDSC contribute to the development of an immunosuppressive TIME in gastric cancer

    Tsutsumi, C; Ohuchida, K; Son, K; Katayama, N; Iwamoto, C; Horioka, K; Shindo, K; Mizuuchi, Y; Nakata, K; Nakamura, M

    CANCER SCIENCE   116   285 - 285   2025.1   ISSN:1347-9032 eISSN:1349-7006

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  • Intratumor <i>Fusobacterium Nucleatum</i> enhance pancreatic cancer progression

    Matsuyoshi, T; Ikenaga, N; Hayashi, M; Oyama, K; Iwamoto, C; Ohuchida, K; Nakata, K; Nakamura, M

    CANCER SCIENCE   116   896 - 896   2025.1   ISSN:1347-9032 eISSN:1349-7006

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  • Dynamic glycolytic reprogramming effects on dendritic cells in pancreatic ductal adenocarcinoma.

    Zhang B, Ohuchida K, Tsutsumi C, Shimada Y, Mochida Y, Oyama K, Iwamoto C, Sheng N, Fei S, Shindo K, Ikenaga N, Nakata K, Oda Y, Nakamura M

    Journal of experimental & clinical cancer research : CR   43 ( 1 )   271   2024.9   ISSN:0392-9078 eISSN:1756-9966

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    Language:English   Publisher:Journal of Experimental and Clinical Cancer Research  

    Background: Pancreatic ductal adenocarcinoma tumors exhibit resistance to chemotherapy, targeted therapies, and even immunotherapy. Dendritic cells use glucose to support their effector functions and play a key role in anti-tumor immunity by promoting cytotoxic CD8<sup>+</sup> T cell activity. However, the effects of glucose and lactate levels on dendritic cells in pancreatic ductal adenocarcinoma are unclear. In this study, we aimed to clarify how glucose and lactate can impact the dendritic cell antigen-presenting function and elucidate the relevant mechanisms. Methods: Glycolytic activity and immune cell infiltration in pancreatic ductal adenocarcinoma were evaluated using patient-derived organoids and resected specimens. Cell lines with increased or decreased glycolysis were established from KPC mice. Flow cytometry and single-cell RNA sequencing were used to evaluate the impacts on the tumor microenvironment. The effects of glucose and lactate on the bone marrow-derived dendritic cell antigen-presenting function were detected by flow cytometry. Results: The pancreatic ductal adenocarcinoma tumor microenvironment exhibited low glucose and high lactate concentrations from varying levels of glycolytic activity in cancer cells. In mouse transplantation models, tumors with increased glycolysis showed enhanced myeloid-derived suppressor cell infiltration and reduced dendritic cell and CD8<sup>+</sup> T cell infiltration, whereas tumors with decreased glycolysis displayed the opposite trends. In three-dimensional co-culture, increased glycolysis in cancer cells suppressed the antigen-presenting function of bone marrow-derived dendritic cells. In addition, low-glucose and high-lactate media inhibited the antigen-presenting and mitochondrial functions of bone marrow-derived dendritic cells. Conclusions: Our study demonstrates the impact of dynamic glycolytic reprogramming on the composition of immune cells in the tumor microenvironment of pancreatic ductal adenocarcinoma, especially on the antigen-presenting function of dendritic cells.

    DOI: 10.1186/s13046-024-03192-8

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  • Combined Autophagy Inhibition and Dendritic Cell Recruitment Induces Antitumor Immunity and Enhances Immune Checkpoint Blockade Sensitivity in Pancreatic Cancer.

    Oyama K, Nakata K, Tsutsumi C, Hayashi M, Zhang B, Mochida Y, Shinkawa T, Hirotaka K, Zhong P, Date S, Luo H, Kubo A, Higashijima N, Yamada Y, Abe T, Ideno N, Koikawa K, Iwamoto C, Ikenaga N, Ohuchida K, Onishi H, Morisaki T, Kuba K, Oda Y, Nakamura M

    Cancer research   84 ( 24 )   4214 - 4232   2024.9   ISSN:0008-5472 eISSN:1538-7445

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    Language:English   Publisher:Cancer Research  

    The effect of immune checkpoint inhibitors is extremely limited in patients with pancreatic ductal adenocarcinoma (PDAC) due to the suppressive tumor immune microenvironment. Autophagy, which has been shown to play a role in antitumor immunity, has been proposed as a therapeutic target for PDAC. In this study, single-cell RNA sequencing of autophagy-deficient murine PDAC tumors revealed that autophagy inhibition in cancer cells induced dendritic cell (DC) activation. Analysis of human PDAC tumors substantiated a negative correlation between autophagy and DC activation signatures. Mechanistically, autophagy inhibition increased the intracellular accumulation of tumor antigens, which could activate DCs. Administration of chloroquine, an autophagy inhibitor, in combination with Flt3 ligand–induced DC infiltration inhibited tumor growth and increased tumor-infiltrating T lymphocytes. However, autophagy inhibition in cancer cells also induced CD8<sup>+</sup> T-cell exhaustion with high expression of immune checkpoint LAG3. A triple-therapy comprising chloroquine, Flt3 ligand, and an anti-LAG3 antibody markedly reduced tumor growth in orthotopic syngeneic PDAC mouse models. Thus, targeting autophagy in cancer cells and activating DCs sensitize PDAC tumors to immune checkpoint inhibitor therapy, warranting further development of this treatment approach to overcome immunosuppression in pancreatic cancer. Significance: Inhibiting autophagy in pancreatic cancer cells enhances intracellular accumulation of tumor antigens to induce dendritic cell activation and synergizes with immunotherapy to markedly inhibit the growth of pancreatic ductal adenocarcinoma.

    DOI: 10.1158/0008-5472.CAN-24-0830

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  • Tumor-associated neutrophils upregulate Nectin2 expression, creating the immunosuppressive microenvironment in pancreatic ductal adenocarcinoma

    Luo, HZ; Ikenaga, N; Nakata, K; Higashijima, N; Zhong, PS; Kubo, A; Wu, CY; Tsutsumi, C; Shimada, Y; Hayashi, M; Oyama, K; Date, S; Abe, T; Ideno, N; Iwamoto, C; Shindo, K; Ohuchida, K; Oda, Y; Nakamura, M

    JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH   43 ( 1 )   258   2024.9   ISSN:0392-9078 eISSN:1756-9966

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    Language:English   Publisher:Journal of Experimental and Clinical Cancer Research  

    Background: Tumor-associated neutrophils (TANs) constitute an abundant component among tumor-infiltrating immune cells and have recently emerged as a critical player in pancreatic ductal adenocarcinoma (PDAC) progression. This study aimed to elucidate the pro-tumor mechanisms of TAN and identify a novel target for effective immunotherapy against PDAC. Methods: Microarray and cytokine array analyses were performed to identify the mechanisms underlying the function of TANs. Human and mouse TANs were obtained from differentiated HL-60 cells and orthotopically transplanted PDAC tumors, respectively. The interactions of TANs with cancer and cytotoxic T-cells were evaluated through in vitro co-culture and in vivo orthotopic or subcutaneous models. Single-cell transcriptomes from patients with PDAC were analyzed to validate the cellular findings. Results: Increased neutrophil infiltration in the tumor microenvironment was associated with poor survival in patients with PDAC. TANs secreted abundant amounts of chemokine ligand 5 (CCL5), subsequently enhancing cancer cell migration and invasion. TANs subpopulations negatively correlated with cytotoxic CD8+ T-cell infiltration in PDAC and promoted T-cell dysfunction. TANs upregulated the membranous expression of Nectin2, which contributed to CD8+ T-cell exhaustion. Blocking Nectin2 improved CD8+ T-cell function and suppressed tumor progression in the mouse model. Single-cell analysis of human PDAC revealed two immunosuppressive TANs phenotypes: Nectin2+ TANs and OLR1+ TANs. Endoplasmic reticulum stress regulated the protumor activities in TANs. Conclusions: TANs enhance PDAC progression by secreting CCL5 and upregulating Nectin2. Targeting the immune checkpoint Nectin2 could represent a novel strategy to enhance immunotherapy efficacy in PDAC.

    DOI: 10.1186/s13046-024-03178-6

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  • Microbiome in the Therapy for the Pancreatic Cancer

    Ikenaga N., Hayashi M., Matsuyoshi T., Iwamoto C., Nakata K., Ohuchida K., Nakamura M.

    Gan to kagaku ryoho. Cancer &amp; chemotherapy   51 ( 6 )   603 - 607   2024.6   ISSN:03850684

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    Publisher:Gan to kagaku ryoho. Cancer &amp; chemotherapy  

    An association between periodontal disease and the development of pancreatic cancer has been pointed out since before. Advances in genome analysis technology have revealed that a pancreatic cancer-specific microbiome is formed in the intestines and tumors of pancreatic cancer patients and modifies the progression of pancreatic cancer. Disturbance of microbiome( dysbiosis)suppresses anti-tumor immunity against pancreatic cancer, promoting cancer progression. Therefore, attempts are being made to correct dysbiosis by administration of probiotics or transplantation of microbiome, which is especially activating immune checkpoint inhibitors against cancer. In addition, specific intratumor bacteria has been identified that create an immunosuppressive microenvironment through crosstalk with pancreatic cancer cells. In the future, analysis of the microbiome distribution in pancreatic cancers may determine the following treatment strategy as an individualized treatment. We hope that innovations in omics technology will reveal more detailed functions of microbiome and lead to the development of effective treatments for pancreatic cancer.

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  • [Microbiome in the Therapy for the Pancreatic Cancer].

    Ikenaga N, Hayashi M, Matsuyoshi T, Iwamoto C, Nakata K, Ohuchida K, Nakamura M

    Gan to kagaku ryoho. Cancer & chemotherapy   51 ( 6 )   603 - 607   2024.6   ISSN:0385-0684

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  • Blockade of histamine receptor H1 augments immune checkpoint therapy by enhancing MHC-I expression in pancreatic cancer cells

    Zhong, P; Nakata, K; Oyama, K; Higashijima, N; Sagara, A; Date, S; Luo, HZ; Hayashi, M; Kubo, A; Wu, CY; He, S; Yamamoto, T; Koikawa, K; Iwamoto, C; Abe, T; Ikenaga, N; Ohuchida, K; Morisaki, T; Oda, Y; Kuba, K; Nakamura, M

    JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH   43 ( 1 )   138   2024.5   ISSN:0392-9078 eISSN:1756-9966

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    Background: Although immune checkpoint blockade (ICB) therapy has proven to be extremely effective at managing certain cancers, its efficacy in treating pancreatic ductal adenocarcinoma (PDAC) has been limited. Therefore, enhancing the effect of ICB could improve the prognosis of PDAC. In this study, we focused on the histamine receptor H1 (HRH1) and investigated its impact on ICB therapy for PDAC. Methods: We assessed HRH1 expression in pancreatic cancer cell (PCC) specimens from PDAC patients through public data analysis and immunohistochemical (IHC) staining. The impact of HRH1 in PCCs was evaluated using HRH1 antagonists and small hairpin RNA (shRNA). Techniques including Western blot, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-PCR), and microarray analyses were performed to identify the relationships between HRH1 and major histocompatibility complex class I (MHC-I) expression in cancer cells. We combined HRH1 antagonism or knockdown with anti-programmed death receptor 1 (αPD-1) therapy in orthotopic models, employing IHC, immunofluorescence, and hematoxylin and eosin staining for assessment. Results: HRH1 expression in cancer cells was negatively correlated with HLA-ABC expression, CD8+ T cells, and cytotoxic CD8+ T cells. Our findings indicate that HRH1 blockade upregulates MHC-I expression in PCCs via cholesterol biosynthesis signaling. In the orthotopic model, the combined inhibition of HRH1 and αPD-1 blockade enhanced cytotoxic CD8+ T cell penetration and efficacy, overcoming resistance to ICB therapy. Conclusions: HRH1 plays an immunosuppressive role in cancer cells. Consequently, HRH1 intervention may be a promising method to amplify the responsiveness of PDAC to immunotherapy.

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  • Tumor-infiltrating monocytic myeloid-derived suppressor cells contribute to the development of an immunosuppressive tumor microenvironment in gastric cancer(タイトル和訳中)

    Tsutsumi Chikanori, Ohuchida Kenoki, Katayama Naoki, Yamada Yutaka, Nakamura Shoichi, Okuda Sho, Otsubo Yoshiki, Iwamoto Chika, Torata Nobuhiro, Horioka Kohei, Shindo Koji, Mizuuchi Yusuke, Ikenaga Naoki, Nakata Kohei, Nagai Eishi, Morisaki Takashi, Oda Yoshinao, Nakamura Masafumi

    Gastric Cancer   27 ( 2 )   248 - 262   2024.3   ISSN:1436-3291

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    胃癌の腫瘍免疫微小環境(TIME)の形成における各種免疫抑制細胞の役割を調べた。病理所見から胃癌および食道扁平上皮癌と診断された患者30例由来の検体を用いて、シングルセルRNAシーケンス(scRNA-seq)などを行い、特定の免疫抑制細胞と胃癌患者の予後との相関を調べた。scRNA-seq解析の結果、腫瘍浸潤単球系骨髄由来抑制細胞(TI-M-MDSC)は、他の免疫抑制細胞よりも免疫抑制機能を持つ遺伝子を高レベルで発現していた。さらに、胃癌組織中のM-MDSCは、隣接する正常組織よりもこれらのマーカーを有意に高発現していた。評価した免疫抑制細胞の中で、M-MDSCは隣接する正常組織と比較して胃癌組織で最も豊富に認められ、M-MDSCの存在は予後不良と強く関連していた。胃癌のM-MDSCと隣接する正常組織で発現が異なる遺伝子として同定されたimmediate early response 3(IER3)は、胃癌患者における独立した予後不良因子であった。

  • Tumor-infiltrating monocytic myeloid-derived suppressor cells contribute to the development of an immunosuppressive tumor microenvironment in gastric cancer

    Tsutsumi, C; Ohuchida, K; Katayama, N; Yamada, Y; Nakamura, S; Okuda, S; Otsubo, Y; Iwamoto, C; Torata, N; Horioka, K; Shindo, K; Mizuuchi, Y; Ikenaga, N; Nakata, K; Nagai, E; Morisaki, T; Oda, Y; Nakamura, M

    GASTRIC CANCER   27 ( 2 )   248 - 262   2024.3   ISSN:1436-3291 eISSN:1436-3305

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    Background: Gastric cancer (GC) is characterized by an immunosuppressive and treatment-resistant tumor immune microenvironment (TIME). Here, we investigated the roles of different immunosuppressive cell types in the development of the GC TIME. Methods: Single-cell RNA sequencing (scRNA-seq) and multiplex immunostaining of samples from untreated or immune checkpoint inhibitor (ICI)-resistant GC patients were used to examine the correlation between certain immunosuppressive cells and the prognosis of GC patients. Results: The results of the scRNA-seq analysis revealed that tumor-infiltrating monocytic myeloid-derived suppressor cells (TI-M-MDSCs) expressed higher levels of genes with immunosuppressive functions than other immunosuppressive cell types. Additionally, M-MDSCs in GC tissues expressed significantly higher levels of these markers than adjacent normal tissues. The M-MDSCs were most enriched in GC tissues relative to adjacent normal tissues. Among the immunosuppressive cell types assessed, the M-MDSCs were most enriched in GC tissues relative to adjacent normal tissues; moreover, their presence was most strongly associated with a poor prognosis. Immediate early response 3 (IER3), which we identified as a differentially expressed gene between M-MDSCs of GC and adjacent normal tissues, was an independent poor prognostic factor in GC patients (P = 0.0003). IER3+ M-MDSCs expressed higher levels of genes with immunosuppressive functions than IER3− M-MDSCs and were abundant in treatment-resistant GC patients. Conclusions: The present study suggests that TI-M-MDSCs, especially IER3+ ones, may play a predominant role in the development of the immunosuppressive and ICI-resistant GC TIME.

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  • Tertiary lymphoid structures correlate with enhancement of antitumor immunity in esophageal squamous cell carcinoma

    Nakamura, S; Ohuchida, K; Hayashi, M; Katayama, N; Tsutsumi, C; Yamada, Y; Hisano, K; Okuda, S; Ohtsubo, Y; Iwamoto, C; Torata, N; Mizuuchi, Y; Shindo, K; Nakata, K; Moriyama, T; Morisaki, T; Oda, Y; Nakamura, M

    BRITISH JOURNAL OF CANCER   129 ( 8 )   1314 - 1326   2023.10   ISSN:0007-0920 eISSN:1532-1827

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    Background: Tertiary lymphoid structures (TLSs) are associated with a favorable prognosis in several cancers. However, the correlation between TLSs and outcomes of esophageal squamous cell carcinoma (ESCC) and the impact of TLSs on the tumor immune microenvironment (TIME) remain unknown. Methods: We pathologically evaluated the significance of TLSs in ESCC focusing on TLS maturation using 180 ESCC specimens and performed single-cell RNA sequencing (scRNA-seq) using 14 ESCC tissues to investigate functional differences of immune cells according to TLS presence. Results: TLS+ cases had better recurrence-free-survival (RFS) (p < 0.0001) and overall survival (OS) (p = 0.0016) compared with TLS- cases. Additionally, mature TLS+ cases had better RFS and OS compared with immature TLS+ cases (p = 0.019 and p = 0.015) and TLS- cases (p < 0.0001 and p = 0.0002). The scRNA-seq showed that CD8+ T cells in TLS+ tumors expressed high levels of cytotoxic signatures and antigen-presentation of dendritic cells (DCs) was enhanced in TLS+ tumors. Immunohistochemistry showed that the densities of tumor-infiltrating CD8+ T cells and DCs were significantly higher in TLS+ tumors than those in TLS- tumors. Conclusions: These data suggest the prognostic and functional significance of TLSs in ESCC and provides new insights into TLSs on the TIME.

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  • Intratumor <i>Fusobacterium nucleatum</i> promotes the progression of pancreatic cancer via the CXCL1-CXCR2 axis

    Hayashi, M; Ikenaga, N; Nakata, K; Luo, HZ; Zhong, PS; Date, S; Oyama, K; Higashijima, N; Kubo, A; Iwamoto, C; Torata, N; Abe, T; Yamada, Y; Ohuchida, K; Oda, Y; Nakamura, M

    CANCER SCIENCE   114 ( 9 )   3666 - 3678   2023.9   ISSN:1347-9032 eISSN:1349-7006

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    Intratumor bacteria modify the tumor immune microenvironment and influence outcomes of various tumors. Periodontal pathogen Fusobacterium nucleatum has been detected in pancreatic cancer tissues and is associated with poor prognosis. However, it remains unclear how F. nucleatum affects pancreatic cancer. Here, we compared clinical features with F. nucleatum colonization in pancreatic cancer tissues. F. nucleatum was detected in 15.5% (13/84) of pancreatic cancer patients. The tumor size was significantly larger in the F. nucleatum-positive group than in the negative group. To clarify the biological effect of intratumor F. nucleatum on pancreatic cancer progression, we performed migration/invasion assays and cytokine array analysis of cancer cells cocultured with F. nucleatum. F. nucleatum promoted CXCL1 secretion from pancreatic cancer cells, leading to cancer progression through autocrine signaling. Intratumor F. nucleatum suppressed tumor-infiltrating CD8+ T cells by recruiting myeloid-derived suppressor cells (MDSCs) to the tumor in an F. nucleatum-injected subcutaneous pancreatic cancer mouse model, resulting in tumor progression. Furthermore, tumor growth accelerated by F. nucleatum was suppressed by MDSC depletion or cytokine inhibitors. Intratumor F. nucleatum promoted pancreatic cancer progression through autocrine and paracrine mechanisms of the CXCL1-CXCR2 axis. Blockade of the CXCL1-CXCR2 axis may be a novel therapeutic approach for patients with intratumor F. nucleatum-positive pancreatic cancer.

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  • 膵癌組織内のFusobacterium nucleatumはCXCL1-CXCR2シグナル伝達軸を介して膵癌の進行を促進する(Intratumor Fusobacterium nucleatum promotes the progression of pancreatic cancer via the CXCL1-CXCR2 axis)

    Hayashi Masataka, Ikenaga Naoki, Nakata Kohei, Luo Haizhen, Zhong PingShan, Date Satomi, Oyama Koki, Higashijima Nobuhiro, Kubo Akihiro, Iwamoto Chika, Torata Nobuhiro, Abe Toshiya, Yamada Yutaka, Ohuchida Kenoki, Oda Yoshinao, Nakamura Masafumi

    Cancer Science   114 ( 9 )   3666 - 3678   2023.9   ISSN:1347-9032

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    歯周病原菌であるFusobacterium nucleatumは膵癌組織内でも発見されており、予後不良と関連していることが知られている。同菌は膵癌進行に重要な役割を果たしているのでないかとの仮説を検証した。膵管腺癌患者の手術検体を調べた。その結果、84名中13名(15.5%)でF.nucleatumが検出された。同菌が陽性の群では陰性の群に比べ腫瘍サイズが有意に大きかった。ヒト膵癌細胞株の培養系では、同菌と共培養することで膵癌細胞からのC-X-Cモチーフケモカインリガンド1(CXCL1)の分泌が促進されることが示された。膵癌マウスモデルの皮下に同菌を注入すると、骨髄由来抑制細胞が腫瘍へ動員されることで腫瘍浸潤T細胞が抑制され、その結果、腫瘍は進行した。骨髄由来抑制細胞を枯渇させるかサイトカイン阻害剤を使用すると、同菌による腫瘍増殖加速作用は抑制された。本研究結果をまとめると、腫瘍内のF.nucleatumは、CXCL1とC-X-Cモチーフケモカイン受容体2(CXCR2)のシグナル伝達軸によるオートクリン・パラクリンの機序を通じて、膵癌の進行を促進していた。腫瘍内にF.nucleatumがみられる膵癌患者に対し、CXCL1-CXCR2軸を遮断する方法は新規な治療アプローチになると考えられた。

  • Involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia lesion of pancreatic cancer invasive front

    Fei, S; Ohuchida, K; Kibe, S; Yan, ZL; Iwamoto, C; Shinkawa, T; Zhang, B; Kawata, J; Abe, T; Ideno, N; Ikenaga, N; Nakata, K; Oda, Y; Nakamura, M

    JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY   149 ( 9 )   5885 - 5899   2023.8   ISSN:0171-5216 eISSN:1432-1335

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    Purpose: This study aimed to demonstrate the involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia (CA-ADM) lesion of invasive front pancreatic ductal adenocarcinoma (PDAC) and investigate the possible mechanism. Methods: Tissue samples from 128 patients with PDAC and 36 LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre mice were analyzed. Immunohistochemical assay was performed using HE, anti-CK19 and anti-amylase to confirm the presence of CA-ADM lesions, using anti-CD34 and anti-CD31 to measure microvessel density (MVD), and using anti-CD68, anti-CD163, anti-iNOS, or anti-MMP9 to evaluate the immune microenvironment. We performed multiplex immunohistochemical assay to detect the co-expression of MMP9 and CD68 on macrophage. We examined clinical outcomes and other clinicopathological factors to determine the significance of high-level MVD of CA-ADM on survival and liver metastasis. We performed tube formation assay to evaluate the effect of macrophage on angiogenic capacity in vitro. Results: Angiogenesis was significantly abundant in CA-ADM lesions compared with that in PDAC lesions in human and mouse tissues. High-level MVD in CA-ADM lesions was an independent predictor of poor prognosis (P = 0.0047) and the recurrence of liver metastasis (P = 0.0027). More CD68-positive and CD163-positive macrophages were detected in CA-ADM lesions than in PDAC. The percentage of CD68-positive macrophages was positively correlated with MVD in CA-ADM lesions. Multiplex-immunostaining revealed that MMP9 was expressed in CD68-positive macrophages of CA-ADM lesions. In CA-ADM lesions, the percentage of macrophages was positively correlated with MMP9 expression, which positively correlated with microvessel density. Conclusion: CA-ADM related angiogenesis is a promising predictive marker for poor prognosis of PDAC and may provide an attractive therapeutic target for PDAC.

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  • Neoadjuvant chemotherapy enhances anti-tumor immune response of tumor microenvironment in human esophageal squamous cell carcinoma

    Okuda, S; Ohuchida, K; Nakamura, S; Tsutsumi, C; Hisano, K; Mochida, Y; Kawata, J; Ohtsubo, Y; Shinkawa, T; Iwamoto, C; Torata, N; Mizuuchi, Y; Shindo, K; Moriyama, T; Nakata, K; Torisu, T; Morisaki, T; Kitazono, T; Oda, Y; Nakamura, M

    ISCIENCE   26 ( 4 )   106480   2023.4   eISSN:2589-0042

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    Although chemotherapy has been an essential treatment for cancer, the development of immune checkpoint blockade therapy was revolutionary, and a comprehensive understanding of the immunological tumor microenvironment (TME) has become crucial. Here, we investigated the impact of neoadjuvant chemotherapy (NAC) on immune cells in the TME of human esophageal squamous cell carcinoma using single cell RNA-sequencing. Analysis of 30 fresh samples revealed that CD8+/CD4+ T cells, dendritic cells (DCs), and macrophages in the TME of human esophageal squamous cell carcinoma showed higher levels of an anti-tumor immune response in the NAC(+) group than in the NAC(−) group. Furthermore, the immune cells of the NAC(+) group interacted with each other resulting in enhanced anti-tumor immune response via various cytokines, including IFNG in CD8+/CD4+ T cells, EBI3 in DCs, and NAMPT in macrophages. Our results suggest that NAC potentially enhances the anti-tumor immune response of immune cells in the TME.

    DOI: 10.1016/j.isci.2023.106480

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  • Single-cell transcriptome analysis reveals functional changes in tumour-infiltrating B lymphocytes after chemotherapy in oesophageal squamous cell carcinoma

    Nakamura, S; Ohuchida, K; Ohtsubo, Y; Yamada, Y; Tsutsumi, C; Okuda, S; Hisano, K; Mochida, Y; Shinkawa, T; Iwamoto, C; Torata, N; Mizuuchi, Y; Shindo, K; Nakata, K; Moriyama, T; Torisu, T; Nagai, E; Morisaki, T; Kitazono, T; Oda, Y; Nakamura, M

    CLINICAL AND TRANSLATIONAL MEDICINE   13 ( 1 )   e1181   2023.1   ISSN:2001-1326

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  • ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via UPR signaling pathway (vol 22, pg 9, 2022)

    Guan, W; Nakata, K; Sagara, A; Iwamoto, C; Endo, S; Matsuda, R; Matsumoto, S; Ikenaga, N; Shindo, K; Moriyama, T; Onishi, H; Ohuchida, K; Oda, Y; Nakamura, M

    PANCREATOLOGY   22 ( 7 )   1059 - 1059   2022.11   ISSN:1424-3903 eISSN:1424-3911

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    Figures in this paper contained western blots where the same membrane was probed repeatedly by the indicated antibodies, occasionally resulting in similar band shapes among the individual panels. Moreover, in Figure 5, results from the same membrane were presented in two columns with the panels for the α-SMA and β-actin blots shown twice for easier comparison. We apologize for any misunderstanding this may have caused.

    DOI: 10.1016/j.pan.2022.08.013

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  • Subtypes in pancreatic ductal adenocarcinoma based on niche factor dependency show distinct drug treatment responses

    Shinkawa, T; Ohuchida, K; Mochida, Y; Sakihama, K; Iwamoto, C; Abe, T; Ideno, N; Mizuuchi, Y; Shindo, K; Ikenaga, N; Moriyama, T; Nakata, K; Oda, Y; Nakamura, M

    JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH   41 ( 1 )   89   2022.3   ISSN:0392-9078 eISSN:1756-9966

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    Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma in which microenvironmental (niche) factors promote PDAC progression. In mouse models, reduction of the stroma increased the proportion of poorly differentiated PDAC with a worse prognosis. Here, we aimed to clarify the effects of stroma on PDAC that may define the PDAC phenotype and induce distinct therapeutic responses. Methods: The molecular features of PDAC based on differentiation grade were clarified by genome and transcriptome analysis using PDAC organoids (PDOs). We identified the dependency on niche factors that might regulate the differentiation grade. A three-dimensional co-culture model with cancer-associated fibroblasts (CAFs) was generated to determine whether CAFs provide niche factors essential for differentiated PDAC. PDOs were subtyped based on niche factor dependency, and the therapeutic responses for each subtype were compared. Results: The expression profiles of PDOs differed depending on the differentiation grade. Consistent with the distinct profiles, well differentiated types showed high niche dependency, while poorly differentiated types showed low niche dependency. The three-dimensional co-culture model revealed that well differentiated PDOs were strongly dependent on CAFs for growth, and moderately differentiated PDOs showed plasticity to change morphology depending on CAFs. Differentiated PDOs upregulated the expression of mevalonate pathway-related genes correlated with the niche dependency and were more sensitive to simvastatin than poorly differentiated PDOs. Conclusions: Our findings suggest that CAFs maintain the differentiated PDAC phenotype through secreting niche factors and induce distinct drug responses. These results may lead to the development of novel subtype-based therapeutic strategies.

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  • ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via UPR signaling pathway

    Guan, W; Nakata, K; Sagara, A; Iwamoto, C; Endo, S; Matsuda, R; Matsumoto, S; Ikenaga, N; Shindo, K; Moriyama, T; Onishi, H; Ohuchida, K; Oda, Y; Nakamura, M

    PANCREATOLOGY   22 ( 1 )   9 - 19   2022.1   ISSN:1424-3903 eISSN:1424-3911

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    Background/objectives: Pancreatic ductal adenocarcinoma (PDAC) is characterized by excessive desmoplasia and autophagy-dependent tumorigenic growth. Pancreatic stellate cells (PSCs) as a predominant stromal cell type play a critical role in PDAC biology. We have previously reported that autophagy facilitates PSC activation, however, the mechanism remains unknown. We investigated the mechanism of autophagy in PSC activation. Methods: We compared gene expression profiles between patient-derived PSCs from pancreatic cancer and chronic pancreatitis using a microarray. The stromal expression of target gene in specimen of PDAC patients (n = 63) was analyzed. The effect of target gene on autophagy and activation of PSCs was investigated by small interfering RNAs transfection, and the relationship between autophagy and ER stress was investigated. We analyzed the growth and fibrosis of xenografted tumor by orthotopic models. Results: In analysis of gene expression microarray, endoplasmic reticulum aminopeptidase 2 (ERAP2) upregulated in cancer-associated PSCs was identified as the target gene. High stromal ERAP2 expression is associated with a poor prognosis of PDAC patients. Knockdown of ERAP2 inhibited unfolded protein response mediated autophagy, and led to inactivation of PSCs, thereby attenuating tumor-stromal interactions by inhibiting production of IL-6 and fibronectin. In vivo, the promoting effect of PSCs on xenografted tumor growth and fibrosis was inhibited by ERAP2 knockdown. Conclusions: Our findings demonstrate a novel mechanism of PSCs activation regulated by autophagy. ERAP2 as a promising therapeutic target may provide a novel strategy for the treatment of PDAC.

    DOI: 10.1016/j.pan.2021.09.012

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  • Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression. Reviewed International journal

    C Iwamoto, K Ohuchida, T Shinkawa, S Okuda, Y Otsubo, T Okumura, A Sagara, K Koikawa, Y Ando, K Shindo, N Ikenaga, K Nakata, T Moriyama, Y Miyasaka, T Ohtsuka, M Eto, K Akashi, M Nakamura.

    Cancer Letters   2021.8

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    Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic reaction caused by cancer-associated fibroblasts (CAFs), which provokes treatment resistance. CAFs are newly proposed to be heterogeneous populations with different functions within the PDAC microenvironment. The most direct sources of CAFs are resident tissue fibroblasts and mesenchymal stem cells, however, the origins and functions of CAF subtypes remain unclear. Here, we established allogeneic bone marrow (BM) transplantation models using spontaneous PDAC mice, and then investigated what subtype cells derived from BM modulate the tumor microenvironment and affect the behavior of pancreatic cancer cells (PCCs). BM-derived multilineage hematopoietic cells were engrafted in recipient pancreas, and accumulated at the invasive front and central lesion of PDAC. We identified BM cells-derived CAFs in tumors. BM-derived macrophages treated with PCC-conditioned media expressed CAF markers. BM-derived macrophages led the local invasion of PCCs in vitro and enhanced the tumor invasive growth in vivo. Our data suggest that BM-derived cells are recruited to the pancreas during carcinogenesis and that the specific subpopulation of hematopoietic stem cells-derived macrophages converted into CAF-like cells, acted as leading cells, and facilitated pancreatic cancer progression. The control of the conversion of BM-derived macrophages into CAF-like cells may be a novel therapeutic strategy to suppress tumor growth.

  • Postmortem interval estimation using the animal model of postmortem gas volume changes. Reviewed International journal

    C Iwamoto, K Ohuchida, M Okumura, Y Usumoto, J Kishimoto, M Murata, N Ikeda, M Hashizume.

    Legal Medicine   2018.5

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  • The BALB/c-specific polymorphic SIRPA enhances its affinity for human CD47, inhibiting phagocytosis against human cells to promote xenogeneic engraftment. Reviewed International journal

    C Iwamoto, K Takenaka, S Urata, T Yamauchi, T Shima, T Kuriyama, S Daitoku, Y Saito, T Miyamoto, H Iwasaki, I Kitabayashi, K Itoh, J Kishimoto, D Kohda, T Matozaki, and K Akashi.

    Exp Hematologist   2014.3

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Presentations

  • MHC提示ペプチド変異を標的とした膵癌治療のパラダイムシフト:早期発見から治療まで

    岩本 千佳, 大内田研宙, 堤親範, 小山虹輝, 久保顕博, 阿部俊也, 渡邉雄介, 井手野昇, 池永直樹, 仲田興平, 中村雅史

    第45回癌免疫外科研究会  2024.5 

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    Event date: 2024.5

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:ワークピア横浜   Country:Japan  

  • MHC class I mutation in CTCs is an indicator of early detection of PDAC and at the same time a possible target of anti-cancer immune reaction. International conference

    Chika Iwamoto, Kenoki Ohuchida, Chikanori Tsutsumi, Koji Shindo, Koki Oyama, Masataka Hayashi, Akihiro Kubo, Nobuhiro Higashijima, Toshiya Abe, Yusuke Watanabe, Noboru Ideno, Naoki Ikenaga, Kohei Nakata, Masafumi Nakamura

    54th American Pancreatic Association 2023 Annual Meeting  2023.11 

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    Event date: 2023.11

    Language:English  

    Venue:San Diego   Country:United States  

    Background: Pancreatic cancer is known to accumulate many mutations, such as KRAS and TP53, in carcinogenesis, but early detection using liquid biopsy is still difficult. We aimed to analyze genetic alternations that accumulate from the precursor lesion to tumorigenesis and cancer progression, including liquid biopsy, and to find key genetic mutations at each stage. We also attempted to investigate effect of those key mutations on tumor microenvironment.
    Methods: Peripheral blood (PB) was collected once a week from KPC mice older than 7-weeks of age until sacrifice and genomic DNA was extracted after hemolysis. For sorting of circulating tumor cells (CTCs) in PB and hemorrhagic ascites of sacrificed KPC mice, anti-mouse CD45 MicroBeads was used. Genomic DNA was extracted from CTCs, and FFPE samples of primary pancreas and liver metastases. We performed exome sequencing with NovaSeq.
    Results: KPC mice were divided into three groups (no primary, primary/no metastasis, and primary/metastasis), and histological images were observed at each stage of cancer progression. When genetic mutations were compared between chronological CTCs of PB and FFPE samples of primary pancreas, we found two mutations, one of which was related to MHC class I. On the other hand, no MHC I mutation were found in the no primary group. When the effect of MHC I mutation on immune cells was evaluated, primary pancreatic tissue showed CD8+ T cell cluster in the regional lymph node compared with no primary group. Two mutations, including MHC I mutation, that appeared at early tumorigenesis were dominant in PB and hemorrhagic ascites, while were not detected in liver metastasis.
    Conclusions: The present data suggest that MHC I mutation which circulate in blood from early carcinogenesis can be an indicator of early detection and that the immune response may eliminate cancer cells with MHC I mutation in liver metastases.

  • CTCsにおけるMHCクラスI変異はPDACの早期発見の指標であると同時に抗腫瘍免疫応答の標的となりうる

    @岩本 千佳,@大内田 研宙,#堤 親範,@進藤 幸治,#小山 虹輝,@林 昌孝,#久保 顕博,#東島亘宏,@阿部 俊也,@渡邉 雄介,@井手野 昇,@池永直樹,@仲田興平,@中村雅史

    第50回日本膵切研究会  2023.8 

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    Event date: 2023.8

    Language:Japanese  

    Country:Japan  

  • 造血幹細胞由来CAF subsetが腫瘍内heterogeneityを高度化する

    岩本千佳, 大内田研宙, 新川智彦, 相良亜希子, 奥田翔, 小山虹輝, 進藤幸治, 池永直樹, 仲田興平, 森山大樹, 中村雅史.

    第52回日本膵臓学会大会  2021.9 

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    Event date: 2021.9

    Language:Japanese  

    Venue:グランドニッコー東京台場   Country:Japan  

  • Development of PDX models with functional human blood and immune systems in pancreatic cancer.

    岩本千佳, 大内田研宙, 新川智彦, 小山虹輝, 奥田翔, 進藤幸治, 池永直樹, 仲田興平, 江藤正俊 中村雅史.

    第76回日本消化器外科学会総会  2021.7 

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    Event date: 2021.7

    Language:Japanese  

    Venue:国立京都国際会館   Country:Japan  

  • HSCs transformed into CAFs in the tumor microenvironment induce the invasion of pancreatic cancer.

    岩本千佳, 大内田研宙, 新川智彦, 大坪慶志輝, 奥田翔, 進藤幸治, 赤司浩一, 大塚隆生, 江藤正俊 中村雅史.

    第75回日本消化器外科学会総会  2020.12 

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    Event date: 2020.12

    Language:Japanese  

    Venue:和歌山ビッグウェーブ   Country:Japan  

  • Human macrophages-derived CAF-like cells lead the invasion of pancreatic cancer. International conference

    C Iwamoto, K Ohuchida, T Shinkawa, Y Ohtsubo, K Shindo, T Moriyama, K Nakata, T Ohtsuka, M Nakamura.

    14th World Congress of the International Hepato-Pancreato-Biliary Association (IHPBA)  2020.11 

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    Event date: 2020.11

    Language:English  

    Venue:オンライン開催   Country:Australia  

  • BM-derived Cells Destruct Basemen Membrane and Induce Local Invasion of Pancreatic Cancer. International conference

    C Iwamoto, K Ohuchida, Y Ando, T Shinkawa, Y Ohtsubo, K Shindo, T Moriyama, K Nakata, K Miyawaki, T Ohtsuka, K Akashi, M Eto, M Nakamura.

    50th Annual Meeting of the American Pancreatic Association  2019.11 

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    Event date: 2019.11

    Language:English  

    Venue:Maui, Hawaii   Country:United States  

  • BM-derived cells multilineage hematopoietic cells that constitute tumor microenvironment lead invasion of pancreatic cancer.

    岩本千佳, 大内田研宙, 安藤陽平, 新川智彦, 大坪慶志輝, 進藤幸治, 森山大樹, 仲田興平, 宮脇恒太, 赤司浩一, 江藤正俊, 中村雅史.

    第78回日本癌学会学術総会  2019.9 

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    Event date: 2019.9

    Language:Japanese  

    Venue:京都国際会議場   Country:Japan  

  • 膵臓に誘導され膵癌微小環境を構成する骨髄由来細胞が膵癌浸潤を制御する

    岩本千佳, 大内田研宙, 武居晋, 進藤幸治, 宮脇恒太, 赤司浩一, 橋爪誠, 江藤正俊 中村雅史.

    第74回日本消化器外科学会総会  2019.7 

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    Event date: 2019.7

    Language:Japanese  

    Venue:グランドプリンスホテル新高輪   Country:Japan  

  • Accumulation and integration of various medical images derived from KPC mice and resected human pancreases. International conference

    C Iwamoto, K Ohuchida, M Hashizume.

    5th International Symposium on the Project “Multidisciplinary Computational Anatomy”  2019.3 

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    Event date: 2019.3

    Language:English  

    Venue:九州大学コラボステーション   Country:Japan  

  • BM-derived cells recruited to the pancreas compose the tumor microenvironment and promote invasion of pancreatic cancer.

    岩本千佳, 大内田研宙, 武居晋, 肥川和寛, 奥村隆志, 遠藤翔, 仲田興平, 宮脇恒太, 村田正治, 江藤正俊, 赤司浩一, 中村雅史, 橋爪誠.

    第77回日本癌学会学術総会  2018.9 

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    Event date: 2018.9

    Language:Japanese  

    Venue:大阪国際会議場   Country:Japan  

  • BM-derived cells recruited to the pancreas constitute the tumor microenvironment and promote invasion of pancreatic cancer. International conference

    C Iwamoto, K Ohuchida, T Okumura, K Koikawa, S Takesue, H Nakayama, S Endo, S Kibe, Y Ando, K Miyawaki, M Murata, K Akashi, M Nakamura, M Hashizume.

    49th Digestive Disease Week  2018.6 

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    Event date: 2018.6

    Language:English  

    Venue:Washington DC   Country:United States  

  • BM-derived Cells Differentiated into Multilineage Hematopoietic Cells Regulate Invasion and Proliferation of Pancreatic Cancer. International conference

    C Iwamoto, K Ohuchida, T Okumura, K Koikawa, S Takesue, H Nakayama, S Endo, S Kibe, Y Ando, K Shindo, K Nakata, K Miyawaki, M Murata, K Akashi, M Nakamura, M Hashizume.

    Pancreas  2018.4 

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    Event date: 2018.4

    Language:English  

    Venue:Baltimore   Country:United States  

  • BM-derived cells are involved in the tumor microenvironment and promote invasion of pancreatic cancer. International conference

    C Iwamoto, K Ohuchida, T Okumura, K Koikawa, S Takesue, H Nakayama, S Endo, S Kibe, Y Ando, T Abe, K Miyawaki, M Murata, K Akashi, M Nakamura, M Hashizume.

    48th Annual Meeting of the American Pancreatic Association  2017.11 

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    Event date: 2017.11

    Language:English  

    Venue:San Diego   Country:United States  

  • 膵癌(基礎) 膵癌治療におけるオートファジー研究 10年先の予後改善を目指して

    仲田 興平, 鐘 坪杉, 小山 虹輝, 相良 亜紀子, 遠藤 翔, 阿部 俊也, 渡邉 雄介, 井手野 昇, 池永 直樹, 岩本 千佳, 田村 公二, 藤本 崇聡, 大内田 研宙, 中村 雅史

    膵臓  2024.7  (一社)日本膵臓学会

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  • 膵癌細胞のAutophagyを標的とした新たな抗腫瘍免疫増強メカニズムの解明

    小山 虹輝, 仲田 興平, 林 昌孝, 伊達 聡美, 持田 郁己, 岩本 千佳, 池永 直樹, 大内田 研宙, 中村 雅史

    膵臓  2023.7  (一社)日本膵臓学会

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  • 膵腫瘍内の歯周病菌Fusobacterium nucleatumはCXCL1-CXCR2シグナルを介して膵癌の進展を促進する

    林 昌孝, 池永 直樹, 仲田 興平, 岩本 千佳, 伊達 聡美, 小山 虹輝, 東島 亘宏, 久保 顕博, 阿部 俊也, 井手野 昇, 中村 雅史

    日本胆膵病態・生理研究会プログラム・抄録集  2023.6  日本胆膵病態・生理研究会

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  • 術前化学療法施行後の膵癌組織内グラム陰性菌が癌微小環境に与える影響の解明

    久保 顕博, 岩本 千佳, 仲田 興平, 小山 虹輝, 堤 親範, 島田 有貴, 山田 裕, 伊達 聡美, 東島 亘宏, 廣高 健斗, 松吉 隆仁, 阿部 俊也, 渡邉 雄介, 井手野 昇, 池永 直樹, 大内田 研宙, 小田 義直, 中村 雅史

    膵臓  2024.7  (一社)日本膵臓学会

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  • 膵疾患と腸内細菌・シンバイオティクス 膵がんは腸内細菌を介して免疫抑制性微小環境を構築する

    池永 直樹, 林 昌孝, 松吉 隆仁, 小山 虹輝, 阿部 俊也, 岩本 千佳, 大内田 研宙, 仲田 興平, 中村 雅史

    膵臓  2024.7  (一社)日本膵臓学会

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  • CTCsにおけるMHCクラスI変異は膵癌の早期発見の指標となりうる

    岩本 千佳, 大内田 研宙, 堤 親範, 小山 虹輝, 久保 顕博, 東島 亘宏, 阿部 俊也, 渡邉 雄介, 井手野 昇, 池永 直樹, 仲田 興平, 中村 雅史

    膵臓  2024.7  (一社)日本膵臓学会

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  • ERAP2は膵癌進展に関わるオートファジー制御遺伝子である

    伊達 聡美, 仲田 興平, 林 昌孝, 小山 虹輝, 岩本 千佳, 池永 直樹, 大内田 研宙, 中村 雅史

    膵臓  2023.7  (一社)日本膵臓学会

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  • パブリックデータを利用した膵癌癌関連線維芽細胞内の遺伝子変化の検討

    東島 亘宏, 仲田 興平, 伊達 聡美, 久保 顕博, 小山 虹輝, 池永 直樹, 岩本 千佳, 大内田 研宙, 中村 雅史

    膵臓  2024.7  (一社)日本膵臓学会

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  • 食道扁平上皮癌のリンパ節転移は,非転移リンパ節においても抑制性の免疫微小環境を形成する

    今村 柾紀, 大内田 研宙, 孫 起和, 小佐井 孝明, 片山 直樹, 堤 親範, 持田 郁己, 中西 芳之, 岩本 千佳, 堀岡 宏平, 進藤 幸治, 小田 義直, 中村 雅史

    日本外科学会定期学術集会抄録集  2025.4  (一社)日本外科学会

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  • 膵癌細胞のオートファジーを標的とした膵癌新規複合免疫療法の開発(Combination of autophagy inhibition, DC induction, and LAG3 blockade induces potent therapeutic response in PDAC)

    小山 虹輝, 仲田 興平, 池永 直樹, 堤 親範, 張 波, 持田 郁己, 廣高 健斗, 阿部 俊也, 井手野 昇, 岩本 千佳, 大内田 研宙, 久場 敬司, 中村 雅史, 池永 直樹

    日本癌学会総会記事  2024.9  (一社)日本癌学会

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  • 腫瘍浸潤単球系骨髄由来抑制細胞は胃癌免疫抑制性微小環境の形成に寄与(Tumor-infiltrating monocytic MDSC contribute to the development of an immunosuppressive TIME in gastric cancer)

    堤 親範, 大内田 研宙, 孫 起和, 片山 直樹, 岩本 千佳, 堀岡 宏平, 進藤 幸治, 水内 祐介, 仲田 興平, 中村 雅史, 大内田 研宙

    日本癌学会総会記事  2024.9  (一社)日本癌学会

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  • 腫瘍内細菌Fusobacterium nucleatumは膵癌の進展を促進する(Intratumor Fusobacterium Nucleatun enhance pancreatic cancer progression)

    松吉 隆仁, 池永 直樹, 林 昌孝, 小山 虹輝, 岩本 千佳, 大内田 研宙, 仲田 興平, 中村 雅史, 池永 直樹, 中村 雅史

    日本癌学会総会記事  2024.9  (一社)日本癌学会

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  • 肝星細胞を標的とした膵癌肝転移に対する新規治療法の開発

    伊達 聡美, 仲田 興平, 小山 虹輝, 東島 亘宏, 久保 顕博, 松吉 隆仁, 廣高 健斗, 岩本 千佳, 池永 直樹, 大内田 研宙, 中村 雅史

    日本外科学会定期学術集会抄録集  2025.4  (一社)日本外科学会

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  • 歯周炎の原因菌はNAC後の膵腫瘍内でマクロファージを免疫抑制性に改変する

    久保 顕博, 岩本 千佳, 仲田 興平, 東島 亘宏, 堤 親範, 島田 有貴, 伊達 聡美, 廣高 健斗, 松吉 隆仁, 阿部 俊也, 渡邉 雄介, 井手野 昇, 池永 直樹, 大内田 研宙, 小田 義直, 中村 雅史

    日本外科学会定期学術集会抄録集  2025.4  (一社)日本外科学会

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  • パブリックデータを利用した膵癌関連線維芽細胞内の遺伝子変化及び膵癌治療

    東島 亘宏, 仲田 興平, 伊達 聡美, 久保 顕博, 小山 虹輝, 池永 直樹, 岩本 千佳, 大内田 研宙, 中村 雅史

    日本外科学会定期学術集会抄録集  2025.4  (一社)日本外科学会

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  • ネオ抗原を標的とした樹状細胞ワクチン療法の強化をめざして

    廣高 健斗, 仲田 興平, 東島 亘宏, 久保 顕博, 小山 虹輝, 伊達 聡美, 岩本 千佳, 阿部 俊哉, 井手野 昇, 池永 直樹, 大内田 研宙, 中村 雅史

    日本外科学会定期学術集会抄録集  2025.4  (一社)日本外科学会

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  • LDHAが骨髄由来抑制細胞の脂質代謝を介して膵癌の免疫抑制性環境の形成に寄与する

    岩本 千佳, 大内田 研宙, 堤 親範, 張 波, 阿部 俊也, 渡邉 雄介, 井手野 昇, 池永 直樹, 仲田 興平, 中村 雅史

    日本外科学会定期学術集会抄録集  2025.4  (一社)日本外科学会

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  • Colitis-associated colon cancerにおける腫瘍浸潤性Bリンパ球の免疫抑制性サブセットの解析

    小佐井 孝彰, 岩本 千佳, 片山 直樹, 堤 親範, 久野 恭子, 孫 紀和, 今村 柾紀, 林田 さゆり, 寅田 信博, 藤本 崇聡, 田村 公二, 永吉 絹子, 水内 祐介, 仲田 興平, 大内田 研宙, 中村 雅史

    日本外科学会定期学術集会抄録集  2025.4  (一社)日本外科学会

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MISC

  • 【膵腫瘍の分子多様性~病態の不均一性を紐解く~】家族性からみた膵癌の分子多様性

    阿部 俊也, 仲田 興平, 岩本 千佳, 渡邉 雄介, 井手野 昇, 池永 直樹, 中村 雅史

    胆と膵   45 ( 7 )   721 - 724   2024.7   ISSN:0388-9408

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    家族性膵癌とは膵癌に罹患した2人以上の第1度近親者がいる家系に発症する膵癌,と定義され,膵癌全体の約10%を占める。網羅的な遺伝子解析により,膵癌発症リスクが濃厚な膵癌家族歴と相関することや,BRCA1/2などのDNA相同組み換え修復に関連する生殖細胞遺伝子バリアントが家族性膵癌の発症に関連することが報告された。一方で家族性膵癌の中で約80%の患者では特定の病的遺伝子が同定されておらず,現在も研究が進められている。個別化医療の実現や膵癌の早期発見のための膵癌高リスク個人のサーベイランスを確立するために,家族性膵癌の多様性のさらなる解明が今後の課題である。(著者抄録)

  • 【腸内細菌叢と癌治療】腸内細菌と膵がん治療

    池永 直樹, 林 昌孝, 松吉 隆仁, 岩本 千佳, 仲田 興平, 大内田 研宙, 中村 雅史

    癌と化学療法   51 ( 6 )   603 - 607   2024.6   ISSN:0385-0684

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    歯周病と膵がん発生の相関は以前より示唆されていた。ゲノム解析の技術進歩により膵がん患者の腸や腫瘍内に膵がん特異的な細菌叢が形成され,膵がんの進展を修飾することが明らかになってきた。腸内細菌の乱れ(ディスバイオーシス)は膵がんに対する腫瘍免疫を抑制し,がんの進展を助長している。そのためプロバイオティクスや菌叢移植でディスバイオーシスを是正し,がんに対する免疫チェックポイント阻害剤を賦活する治療が試みられている。また,膵がん細胞とのクロストークから免疫抑制性微小環境を構築している特定の腫瘍内細菌も明らかにされている。将来的には膵がん腫瘍内の菌叢分布を解析し,解析結果に応じた個別化治療も検討されると思われる。オミックス技術の革新で,より詳細な腸内細菌の機能が明らかとなり,有効な膵がん治療が開発されることを期待する。(著者抄録)

  • 【膵癌基礎研究の最前線RELOADED】Humanizedマウスを用いた膵癌PDXモデルの作製と膵癌微小環境の解析

    岩本 千佳, 大内田 研宙, 池永 直樹, 仲田 興平, 中村 雅史

    胆と膵   45 ( 2 )   111 - 115   2024.2   ISSN:0388-9408

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    Language:Japanese   Publisher:医学図書出版(株)  

    膵癌をはじめとする悪性腫瘍の病態理解や新規治療法の開発には,マウスモデルは必要不可欠であり,その中でも異種移植モデルは欠かせないプラットフォームである。これまでに培養細胞を移植するcell line-derived xenograft(CDX)モデルや患者由来切除組織片を移植するpatient-derived xenograft(PDX)モデルが開発されてきた。これにより,腫瘍の発生・増大,遺伝子発現解析,バイオマーカー探索,薬剤の有効性評価など,癌研究において新たな知見が見出されており,適切な解析系を選択することが重要であると言える。近年,悪性腫瘍に対する第4の治療法として脚光を浴びている癌免疫療法研究の解析ツールとして,膵癌のhumanized PDXマウスモデルを開発した。従来のマウスモデルと異なり,マウス内にヒト造血・免疫系細胞が再構築されているため,癌免疫療法の解析に必要な免疫応答の評価が可能なモデルとして期待できる。しかし,膵癌humanized PDXモデルにおいて生着した免疫細胞の割合がヒト生体内でみられる割合とは異なることやマウスモデルの安定的な供給には,さらなる改良が必要である。(著者抄録)

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Professional Memberships

  • Japanese Cancer Association

  • Japan Pancreas Society

  • The Japanese Society of Hematology

  • The Japanese Society of Gastroenterological Surgery

Research Projects

  • 膵癌の免疫微小環境の2段階改変を伴うImmuno-ablation therapyの開発

    Grant number:25H01062  2025.4 - 2028.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (A)

    中村 雅史, 岩本 千佳, 大内田 研宙, 田中 真二, 石川 文彦, 仲田 興平, 岡野 栄之, 国崎 祐哉, 池永 直樹

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    Grant type:Scientific research funding

    膵癌は早期発見が困難でかつ治療抵抗性の極めて予後不良な癌である。これまでにcold tumorをhot tumorに変える試みが多くなされているが、確立された改変法はない。そこで我々は、免疫細胞の侵入の障壁となる間質成分の破壊・減少、および腫瘍組織内への免疫細胞の集積という2段階改変を惹起する二刀流CAR-T(Musashi CAR-T)細胞療法により、免疫微小環境同時改変を通じたImmuno-ablation therapyを確立しようと考えた。この免疫環境下で既存の抗がん剤治療やICI治療を行うことによりその効果を最大限に引き出し膵癌の根治を目指す。

  • 腹膜播種形成において、中皮細胞由来apCAFは新規キープレイヤーとなりうるか?

    Grant number:25K11845  2025.4 - 2028.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    小薗 真吾, 岩本 千佳, 肥川 和寛

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    Grant type:Scientific research funding

    消化器癌の腹膜播種は予後不良であり、その病態に即した特異的な治療法は存在しない。近年、腫瘍間質を構成する癌関連線維芽細胞(CAF)の中でも、CD74およびMHCクラスIIを発現するantigen-presenting CAF(apCAF)の存在が報告され、中皮細胞由来であることが示唆されているが、その機能は未解明である。本研究では、腹膜中皮細胞が癌細胞との相互作用によりapCAFへと誘導され、免疫抑制性微小環境を形成して腹膜播種に関与することを示し、その機序を明らかにすることで、腹膜播種に対する新たな制御戦略の創出を目指す。

  • 空間遺伝子解析を用いた胃癌免疫抑制ニッチの解明と層別化治療開発

    Grant number:25K10537  2025.4 - 2028.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    貞苅 良彦, 進藤 幸治, 岩本 千佳, 中村 祥一

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    Grant type:Scientific research funding

    近年、胃癌に対する免疫療法の適応が拡大しつつあるが、その奏効率は十分ではなく、治療抵抗性が大きな課題となっている。シングルセルRNAシークエンス(scRNAseq)解析により、腫瘍微小環境(TIME)の高度な不均一性が治療抵抗性に影響を与えることが明らかになっている。また、空間解析技術の発展により、異なる細胞種の相互作用によって形成される「免疫抑制ニッチ」が治療抵抗性に関与する可能性が示唆されている。本研究では、scRNAseq解析に加え、空間トランスクリプトーム解析を統合することで、胃癌の組織型ごとの免疫抑制ニッチを特定し、新たな層別化治療の提案を目指す。

  • 腫瘍浸潤白血球に高度に濃縮されるCHIPの膵癌微小環境に対する潜在的な影響の解明

    Grant number:24K11869  2024 - 2026

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    岩本 千佳, 中村 雅史, 進藤 幸治, 藤本 崇聡, 新川 智彦

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    Authorship:Principal investigator  Grant type:Scientific research funding

    CHIPは血液腫瘍や炎症性疾患など幅広い病態と関連付けられており、CHIP変異は検出される遺伝子や細胞により臨床的意義が異なる。固形腫瘍におけるCHIPの発生率は癌腫によって異なることが言われ始めているが、固形腫瘍におけるCHIPの影響うは現在のところ殆ど解明されていない。そこで我々は、膵癌のCHIPを詳細に解明することで、病態形成や腫瘍免疫微小環境に新たな知見をもたらすだけでなく、がん免疫療法の効果増大や持続性の改良を目指す。

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  • 膵癌に対する抗腫瘍免疫抑制性環境の改変を目指したCAR-T療法の開発

    Grant number:22H00480  2022.4 - 2025.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (A)

    中村 雅史, 岩本 千佳, 大内田 研宙, 竹中 克斗, 村田 正治, 仲田 興平, 森崎 隆

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    Grant type:Scientific research funding

    膵癌が治療抵抗性である要因として腫瘍免疫抑制的な環境があるが、癌間質細胞(CAF)が原因の一つであると考えられている。また、CAFのheterogeneityの解明が進み、膵癌でも複数の機能的CAFクラスターの存在が明らかにされてきたが、腫瘍免疫抑制の要因となる機能的CAFクラスターは同定されていない。本研究では抗腫瘍免疫抑制的な環境を構築する特定のCAFクラスターを同定し、そのようなCAFクラスターを標的とするキメラ抗原受容体T細胞(CAR-T)療法を開発する。

    CiNii Research

  • 膵癌におけるマクロファージ免疫チェックポイントdual mechanismの解明

    Grant number:21K08779  2021 - 2023

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    岩本 千佳, 大内田 研宙

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    Authorship:Principal investigator  Grant type:Scientific research funding

    膵癌における有効なマクロファージ免疫チェックポイント分子やその作用機序は殆ど解明されていない。そこで"Don't eat me" signal と"Eat me" signalのdual mechnismをもつマクロファージ免疫チェックポイントによる膵癌微小免疫環境の維持機構を解明する。腫瘍内マクロファージを中心とした免疫監視機構の制御により、抗腫瘍効果を回復させる新規免疫療法の確立を目指す。

    CiNii Research

  • Construction of drug discovery library using PDX-3D method and discovery of novel therapeutic agents for pancreatic cancer

    Grant number:20H03754  2020.4 - 2023.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    MIZUMOTO Kazuhiro

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    Grant type:Scientific research funding

    We developed the original drug screening using fat-droplet staining in pancreatic stellate cells to develop new stromal-targeted therapeutics in pancreatic cancer. The identified candidate drugs inhibited cancer-stromal interactions and showed marked tumor shrinkage when combined with immune checkpoint inhibitors, suggesting that they could enhance tumor immunity.

    CiNii Research

  • Gene expression mapping of esophageal cancer microenvironment by spatial transcriptomics

    Grant number:20K09080  2020.4 - 2023.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    INOUE Shigetaka

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    Grant type:Scientific research funding

    In recent years, single-cell analysis has attracted attention for elucidating the mechanisms of cancer invasion and metastasis. we initiated this study using Visium, a new technology, to create a gene expression map consistent with conventional pathomorphology and to elucidate the tumor microenvironment. Data from esophageal cancer samples show that chemotherapy reduces the immunosuppressive capacity of regulatory T cells, cytotoxic T cells evade exhaustion, and helper T cells are induced to become more memory-intensive and prevent exhaustion. These results suggest that chemotherapy may enhance anti-tumor immunity by immune cells in esophageal cancer.

    CiNii Research

  • 膵癌進展を促す骨髄由来細胞による癌細胞clonalityの選択機序解明とその制御

    Grant number:18K16366  2018 - 2020

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Early-Career Scientists

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • 膵癌の発癌・進展に関わる骨髄由来leading cellの同定と新規治療法の開発

    Grant number:16K19937  2016 - 2017

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Young Scientists (B)

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • 膵癌浸潤/転移を導く骨髄由来leading cellの同定とその制御法の開発

    Grant number:15H06480  2015 - 2016

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Research Activity start-up

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    Authorship:Principal investigator  Grant type:Scientific research funding

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