Language：English   Publishing type：Research paper (scientific journal)   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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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   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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Language：English   Publishing type：Research paper (scientific journal)   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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancer Science  

Patients with colorectal cancer (CRC) following renal transplantation require long-term immunosuppressants to prevent graft rejection. However, the impact of these immunosuppressants on the tumor immune microenvironment and the roles of immune cells within it remain poorly understood. We conducted comprehensive single-cell RNA sequencing on tumor and normal tissues from four CRC patients post renal transplantation and compared these with published data from 23 non-transplant CRC patients. We set four groups for detailed comparative analysis based on the renal transplantation status and tissue origin: non-renal transplantation normal (nRT_Normal), non-renal transplantation tumor (nRT_Tumor), renal transplantation normal (RT_Normal), renal transplantation tumor (RT_Tumor). Our analysis revealed significant tumor immune microenvironment landscape alterations in the transplantation group. CD8⁺effector T cells of RT_Tumor showed significantly diminished cytotoxicity and tumor neoantigen recognition (p < 0.0001), while CD4⁺FOXP3 regulatory T cells of RT_Tumor displayed a higher inhibitory score (p < 0.05), indicating preserved immunomodulatory potential compared with non-transplant CRC. Notably, significantly increased CTLA4 expression in T cells of RT_Tumor was found and testified (p < 0.05). Our findings provide novel mechanistic insights for understanding the immune landscape in renal transplant recipients with CRC and pave the way for potential immunotherapeutic strategies that may improve survival and quality of life for this patient population.

DOI： 10.1111/cas.16409

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：John Wiley & Sons Australia, Ltd  

腎移植を受けた大腸癌患者から採取した癌組織のシングルセルレベルでの細胞構成、転写プロファイル、免疫ランドスケープを解析することで、腎移植後の大腸癌における分子生物学的および免疫学的特徴について検討した。腎移植を受けた大腸癌患者4例の腫瘍組織と正常組織に対して包括的なシングルセルRNAシーケンス解析を実施し、腎移植を受けていない大腸癌患者23例の既報データと比較した。腎移植の有無と組織の起源に基づいて、詳細な比較分析のための4群を設定した:腎移植非実施正常組織(nRT_Normal)、腎移植非実施腫瘍組織(nRT_Tumor)、腎移植実施正常組織(RT_Normal)、腎移植実施腫瘍組織(RT_Tumor)。その結果、腎移植群において腫瘍免疫微小環境の顕著な変化が明らかになった。RT_TumorにおけるCD8+エフェクター細胞は、細胞傷害性および腫瘍新規抗原認識能が有意に低下していた(p<0.0001)。RT_TumorにおけるCD4+FOXP3制御性T細胞がより高い抑制スコアを示したことから、nRT_Tumorと比較して免疫調節能が保たれていることが示唆された。さらに、RT_TumorにおけるT細胞においてCTLA4の発現が有意に増加していた。以上より、大腸癌を合併する腎移植レシピエントの免疫環境に関する新たなメカニズムが明らかになった。

Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   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⁺ 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⁺ 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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Language：English   Publishing type：Research paper (scientific journal)   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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancer Science  

Preoperative treatment is commonly carried out for borderline resectable pancreatic ductal adenocarcinoma (PDAC). However, the relationship between the combination of immune cells in the tumor microenvironment and their intratumoral heterogeneity along with their association with histological findings remains unclear, especially in patients receiving preoperative chemotherapy. We aimed to explore the therapeutic strategies for patients with PDAC with poor prognosis after receiving chemotherapy based on histological and immunological microenvironmental classifications. We investigated the correlation between the prognosis and histological immune microenvironmental factors of patients who initially underwent surgery (n = 100) and were receiving gemcitabine plus nab-paclitaxel (GEM + nabPTX) as preoperative chemotherapy (n = 103). Immune profiles were generated based on immune cell infiltration into the tumor, and their correlation with patient outcomes and histological features was analyzed. Tumor-infiltrating neutrophils (TINs) were identified as independent poor prognostic factors using multivariate analysis in both surgery-first and preoperative chemotherapy groups. The patients were further classified into four groups based on immune cell infiltration into the tumor. Patients with high CD15 infiltration into the tumor and immature stroma at the cancer margins showed the worst prognosis in the preoperative chemotherapy group. The analysis of mRNA expression and immunohistochemical features revealed that CXCR2, the receptor for CXCL8, was correlated with disease-free and overall survival. We inferred that patients with immature stroma at the margins and high infiltration of CD15⁺ neutrophils within the tumor showed the worst prognosis and they could particularly benefit from treatment with inhibitors targeting CXCR2 or CXCL8.

DOI： 10.1111/cas.16060

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Pancreas Society  

<p>A 48-year-old woman with abdominal pain presented for a detailed examination because abdominal ultrasonography revealed a mass in the head of the pancreas. Contrast-enhanced CT scan showed a 15mm solid mass with delayed enhancement on the ventral side of the pancreatic head and T2-weighted MRI showed a high intensity mass. EUS showed a 15mm hypoechoic well-circumscribed mass in the pancreatic head. Based on these imaging findings, a pancreatic tumor was suspected, possibly a neuroendocrine tumor or solid pseudopapillary tumor, but further diagnosis was difficult. Therefore, EUS-FNB was performed and histopathology showed proliferated spindle cells arranged in fascicles with positive for protein S-100 on immunohistostaining, consistent with a pancreatic Schwannoma. With the history of abdominal pain, a decision was made to proceed with surgery and laparoscopic enucleation successfully performed. Final histopathological evaluation showed a pancreatic Schwannoma without malignancy. She was discharged on postoperative day 12 without complications and has no abdominal pain or recurrence 1 year postoperatively.</p>

DOI： 10.2958/suizo.38.279

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Modern Pathology  

Mixed-type ampullary carcinoma is a subtype that combines intestinal-type (I-type) and pancreatobiliary-type (PB-type) lesions, but few studies have examined its clinicopathologic features and genetic alterations. The differences in genetic alterations between mixed type and other subtypes, as well as the genetic differences between I-type and PB-type lesions in the mixed type, remain unclear. In this study, we compared the clinicopathologic features and prognosis of 110 ampullary carcinomas classified by hematoxylin and eosin and immunohistochemical staining as follows: 63 PB-type, 35 I-type, and 12 mixed-type carcinomas. A comparative analysis of genetic mutations by targeted sequencing of 24 genes was also performed in 3 I-type cases, 9 PB-type cases, and I and PB-type lesions of 6 mixed-type cases. The mixed subtype had a poorer prognosis than the other subtypes, and there was also a similar tendency in the adjuvant group (n = 22). A total of 49 genetic mutations were detected in all 18 lesions for which genetic alteration was analyzed. No genetic mutations specific to the mixed type were found, and it was not possible to determine genetically whether the mixed type had originally been I or PB type. However, 5 of 6 cases had mutations common to both I and PB-type lesions, and additional mutations were found only in either I or PB-type lesions. In support of this, the mixed type more frequently exhibited genetic heterogeneity intratumorally than the other subtypes. Mixed-type tumors are histologically, immunohistochemically, and genetically heterogeneous, and this heterogeneity is associated with poor prognosis and may affect treatment resistance.

DOI： 10.1016/j.modpat.2023.100181

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本消化器外科学会  

症例は61歳の女性で,貧血の精査で行った経口ダブルバルーン内視鏡で空腸中部に頂部に潰瘍を伴う無茎性の隆起性病変を認めた.黒色便,貧血の改善のため腹腔鏡下小腸部分切除を施行した.病理診断で炎症細胞浸潤および一部小葉状の毛細血管増生の所見を認め,pyogenic granulomaと診断した.術後は貧血の改善を認めた.Pyogenic granulomaは皮膚や口腔内に好発する肉芽組織型血管腫であり,消化管での発生はまれである.易出血性であり消化管出血の原因となりうることから原因不明の消化管出血は本症が原因であることがある.(著者抄録)

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本大腸肛門病学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Virchows Archiv  

Mucinous cystic neoplasm (MCN) of the pancreas rarely progresses to invasive carcinoma, but few studies have analyzed genomic alterations involved in its malignant transformation. The relationships of ring finger protein 43 (RNF43) mutations with cytological atypia, RNF43 protein expression, and Wnt signaling proteins in MCN remain unclear. This study included 106 MCN cases, classified into 89 low-grade dysplasia (LG), 9 high-grade dysplasia (HG), and 8 invasive carcinoma (INV). We analyzed HG/INV and LG lesions of 9 HG/INV cases and LG lesions of 9 LG cases using targeted sequencing and confirmed the protein expression of RNF43 and β-catenin. The frequency of RNF43 mutations was significantly higher in HG/INV cases than in LG cases. Furthermore, HG/INV lesions (56%) and LG lesions (33%) of HG/INV cases possessed RNF43 mutation, whereas no such mutation was detected in any LG cases. The expression of RNF43 was reduced in 71% of HG/INV cases and significantly correlated with histological grade and aberrant expression of β-catenin. In 3 of 5 RNF43-mutated cases, the expression of RNF43 was reduced, but there was no significant correlation between RNF43 mutation and protein expression. MCNs frequently harbored KRAS mutations, at rates of 100% in HG/INV lesions and 50% in LG lesions of HG/INV and LG cases. There was no significant difference in mutation frequency in LG lesions between HG/INV and LG cases. These results suggest that RNF43 mutations may be involved in and predictive of malignant transformation from an early stage of MCN.

DOI： 10.1007/s00428-022-03277-9

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本消化器外科学会  

症例は69歳の女性で,食道胃接合部癌に対する手術時に,肝被膜下に5mm弱の白色結節が散在していた.術中迅速診断で腺癌と診断されたため,手術適応外と判断した.化学療法を施行し,その後の審査腹腔鏡時に再度切除した組織で胆管過誤腫と診断され,後日改めて根治術を施行した.本症例は,初回手術時に採取した組織片が小さく,超音波凝固切開装置による熱変性による細胞の変形が,病理診断の大きな障害になったと考えられる.加えて,原発の食道胃接合部癌が高分化型であり,異型が比較的弱い病変であったことも一因といえる.消化器癌に併存した肝腫瘍の診断において,当疾患の存在も念頭におき,微小な病変であってもその組織構築や細胞形態の維持が不十分となり病理診断に影響しないように,アーチファクトが加わらない美麗な標本を十分量採取するよう心がけるべきである.(著者抄録)

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Language：Japanese   Presentation type：Oral presentation (general)  

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Language：Japanese   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

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