Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Kentaro TANAKA Last modified date:2020.07.02

Assistant Professor / Internal Medicine / Respiratory Medicine / Kyushu University Hospital

1. Kunihiro Suzuki, Toyoshi Yanagihara, Koichiro Matsumoto, Hitoshi Kusaba, Takuji Yamauchi, Yuki Ikematsu, Kentaro Tanaka, Kohei Otsubo , Hiroyuki Inoue, Yasuto Yoneshima, Eiji Iwama, Masako Arimura-Omori, Eiji Harada, Naoki Hamada, Isamu Okamoto, Yoichi Nakanishi, Immune-checkpoint Profiles for T Cells in Bronchoalveolar Lavage Fluid of Patients With Immune-Checkpoint Inhibitor-Related Interstitial Lung Disease, Interntional Immunology, 2020.04.
2. Hibiki Udagawa, Hiroaki Akamatsu, Kentaro Tanaka, Masayuki Takeda, Shintaro Kanda, Keisuke Kirita, Shunsuke Teraoka, Kazuhiko Nakagawa, Yutaka Fujiwara, I. Yasuda, Sumiko Okubo, Masayuki Shintani, Matthew P. Kosloski, Charity Scripture, Tomohide Tamura, I. Okamoto, Phase I safety and pharmacokinetics study of rovalpituzumab tesirine in Japanese patients with advanced, recurrent small cell lung cancer, Lung Cancer, 10.1016/j.lungcan.2019.07.025, 135, 145-150, 2019.09, Objectives: Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) on small cell lung cancer (SCLC) tumors, is internalized and releases the toxin pyrrolobenzodiazepine to induce cell death. This open label phase I study was the first study of Rova-T in Japanese patients. The aim of this study was to evaluate, safety, pharmacokinetics, and preliminary efficacy of Rova-T in Japanese patients with advanced recurrent SCLC. Materials and methods: Patients received Rova-T (0.2 or 0.3 mg/kg) by intravenous infusion on Day (D) 1 of each 6-week cycle for 2 doses and dexamethasone (8 mg BID oral) on D-1, D1, and D2 of each 6-week cycle. Retreatment with Rova-T was permitted for patients who tolerated their initial doses and then progressed after disease control (defined as stable disease or better) was observed for at least 12 weeks after their last dose of Rova-T. Results: Rova-T exhibited toxicity that was generally manageable in Japanese patients (N = 29). No dose-limiting toxicities were experienced. The most common treatment-related adverse events (≥25% of patients, all grades) were platelet count decreased, pleural effusion, peripheral edema, aspartate aminotransferase increased, white blood cell count decreased, neutrophil count decreased, alanine aminotransferase increased, hypoalbuminaemia, anemia and decreased appetite. Safety and pharmacokinetics exposures were similar to previous observations in non-Japanese populations. Per investigator assessment of DLL3 high patients, 17% (3/18) had confirmed partial responses, and the disease control rate was 56%, mPFS was 2.9 months, and mOS was 7.4 months. Conclusions: These preliminary data support further exploration of Rova-T treatment in Japanese patients with SCLC in global studies. This trial was registered with as NCT03086239..
3. Yuki Ikematsu, Kentaro Tanaka, Toyoshi Yanagihara, Renpeng Liu, Hiroyuki Inoue, Yasuto Yoneshima, Keiichi Ota, Eiji Iwama, Shohei Takata, Kentaro Hata, Yuriko Takahata, Hiroshi Wataya, Yoichi Nakanishi, Isamu Okamoto, Immune checkpoint protein and cytokine expression by T lymphocytes in pleural effusion of cancer patients receiving anti–PD-1 therapy, Lung Cancer, 10.1016/j.lungcan.2019.10.011, 138, 58-64, 2019.12, Objectives: Pleural effusion (PE) occasionally develops in cancer patients during treatment with antibodies to programmed cell death–1 (PD-1) or to its ligand PD-L1 (hereafter, αPD-1 therapy). Such effusion often contains infiltrated mononuclear cells, although the types of immune cell present as well as the outcome of such patients have remained unclear. Materials and methods: We performed a multi-institutional, observational study to examine the clinical outcome of patients who develop PE after the onset of αPD-1 therapy. We compared the immune cell profiles and the immune status of lymphocytes in PE as determined by flow cytometry between nine patients who developed effusion during αPD-1 therapy (αPD-1 group) and 15 patients who developed PE during treatment with other anticancer agents (control group). Results: Most mononuclear cells in PE were lymphocytes in both the αPD-1 and control groups. The frequency of both CD4+ and CD8+ T lymphocytes expressing the immune checkpoint proteins TIM-3 or TIGIT as well as that of CD8+ T lymphocytes expressing PD-L1 were increased in the αPD-1 group compared with the control group. αPD-1 therapy continued for a substantial period after the emergence of PE in six of the nine patients in the αPD-1 group, and the frequency of CD4+ T lymphocytes in PE expressing the immune checkpoint protein LAG-3 or the cytokine interkeukin-17 was lower for these patients than for those who did not receive a sustained treatment benefit. Conclusion: Our results suggest a clinical benefit of continuing αPD-1 therapy in some patients who develop PE. We found that infiltrating T lymphocytes in PE manifest a more exhausted phenotype during αPD-1 therapy than during treatment with other cancer drugs, with subpopulations of these cells characterized by specific immune checkpoint protein and cytokine expression profiles possibly contributing to the antitumor immune response..
4. Kazuki Takada, Gouji Toyokawa, Yasuto Yoneshima, Kentaro Tanaka, Isamu Okamoto, Mototsugu Shimokawa, Sho Wakasu, Akira Haro, Atsushi Osoegawa, Tetsuzo Tagawa, Yoshinao Oda, Yoichi Nakanishi, Masaki Mori, 18F-FDG uptake in PET/CT is a potential predictive biomarker of response to anti-PD-1 antibody therapy in non-small cell lung cancer, Scientific reports, 10.1038/s41598-019-50079-2, 9, 1, 2019.12, To examine the association between 18F-fluorodeoxyglucose (18F-FDG) uptake in positron emission tomography/computed tomography (PET/CT) and the response to anti-programmed cell death-1 (PD-1) monoclonal antibody therapy in non-small cell lung cancer (NSCLC) patients, 89 patients with advanced or recurrent NSCLC were retrospectively analysed. Maximum standardized uptake value (SUVmax) in 18F-FDG PET/CT and the response to anti-PD-1 antibodies were recorded. A cut-off value of SUVmax was determined by receiver operating characteristic curve analysis for patient stratification. Among the 89 patients evaluated, 24 were classified as responders (all partial response), and 65 as non-responders. The average SUVmax of the responders was 15.60 (range, 6.44–51.10), which was significantly higher than that of the non-responders (11.61; range, 2.13–32.75; P = 0.0168, Student’s t-test). The cut-off SUVmax value selected for stratification was 11.16 (sensitivity and specificity, 0.792 and 0.585, respectively). The response rate of patients with SUVmax value ≥ 11.16 (41.3% [19/46]) was significantly higher than that of patients with SUVmax < 11.16 (11.6% [5/43], P = 0.0012, Chi-squared test). The SUVmax in 18F-FDG PET/CT is a potential predictive marker of response to anti-PD-1 antibody therapy in NSCLC patients. Further prospective studies of large populations are necessary to validate these results..
5. Hirono Tsutsumi, Yasuto Yoneshima, Keiichi Ota, Kohei Otsubo, Eiji Iwama, Hiroyuki Inoue, Kentaro Tanaka, Yoichi Nakanishi, Isamu Okamoto, Multiclonality and Radiosensitivity of Granulocyte-colony Stimulating Factor-Producing Lung Adenocarcinoma Positive for an Activating EGFR Mutation, Clinical Lung Cancer, 10.1016/j.cllc.2019.09.001, 21, 1, e21-e24, 2020.01.
6. Ryoji Kato, Hidetoshi Hayashi, Yasutaka Chiba, Eriko Miyawaki, Junichi Shimizu, Tomohiro Ozaki, Daichi Fujimoto, Ryo Toyozawa, Atsushi Nakamura, Toshiyuki Kozuki, Kentaro Tanaka, Shunsuke Teraoka, Kazuhiro Usui, Kazumi Nishino, Osamu Hataji, Keiichi Ota, Noriyuki Ebi, Sho Saeki, Yuki Akazawa, Motoyasu Okuno, Nobuyuki Yamamoto, Kazuhiko Nakagawa, Propensity score-weighted analysis of chemotherapy after PD-1 inhibitors versus chemotherapy alone in patients with non-small cell lung cancer (WJOG10217L), Journal for immunotherapy of cancer, 10.1136/jitc-2019-000350, 8, 1, 2020.02, BACKGROUND: Studies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response for non-small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of chemotherapy after PD-1 inhibitor treatment (CAP) compared with chemotherapy alone. METHODS: We conducted a retrospective observational cohort study for patients treated at 47 institutions across Japan between April 1, 2014 and July 31, 2017. Eligible patients had advanced or recurrent NSCLC who have undergone chemotherapy. Patients subsequently treated with chemotherapy (docetaxel with or without ramucirumab, S-1 or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort) were included. The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors. RESULTS: A total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics-including age, histology, EGFR or ALK genetic alterations, and brain metastasis-differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 11.0% for the control cohort (ORR ratio 1.71; 95% CI 1.19 to 2.46; p=0.004). IPW-adjusted Kaplan-Meier curves showed that median progression-free survival (PFS) for the CAP and control cohorts was 2.8 and 2.7 months (IPW-adjusted HR 0.95; 95% CI 0.80 to 1.12; p=0.55), and median overall survival (OS) was 9.2 and 10.4 months (IPW-adjusted HR 1.05; 95% CI 0.86 to 1.28; p=0.63), respectively. CONCLUSIONS: After accounting for selection bias by propensity score analysis, CAP showed a significantly higher ORR compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into a PFS or OS advantage, suggesting that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit..
7. Akamatsu H, Ninomiya K, Kenmotsu H, Morise M, Daga H, Goto Y, Kozuki T, Miura S, Sasaki T, Tamiya A, Teraoka S, Tsubata Y, Yoshioka H, Hattori Y, Imamura CK, Katsuya Y, Matsui R, Minegishi Y, Mizugaki H, Nosaki K, Okuma Y, Sakamoto S, Sone T, Tanaka K, Umemura S, Yamanaka T, Amano S, Hasegawa K, Morita S, Nakajima K, Maemondo M, Seto T, Yamamoto N, The Japanese Lung Cancer Society Guideline for non-small cell lung cancer, stage IV., International Journal of Clinical Oncology, 2019.07, According to rapid development of chemotherapy in advanced non-small cell lung cancer (NSCLC), the Japan Lung Cancer Society has been updated its own guideline annually since 2010. In this latest version, all of the procedure was carried out in accordance with grading of recommendations assessment, development and evaluation (GRADE) system. It includes comprehensive literature search, systematic review, and determination of the recommendation by multidisciplinary expert panel which consisted of medical doctors, pharmacists, nurses, statisticians, and patients from patient advocacy group. Recently, we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors. Thus, the guideline proposes to categorize patients into three entities: (1) driver oncogene-positive, (2) PD-L1 ≥ 50%, and (3) others. Based on this subgroup, 31 clinical questions were described. We believe that this attempt enables clinicians to choose appropriate treatment easier. Here, we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC, stages IV..
8. Yasuto Yoneshima, Kentaro Tanaka, Yoshimasa Shiraishi, Kojiro Hata, Hiroyuki Watanabe, Taishi Harada, Kohei Otsubo, Eiji Iwama, Hiroyuki Inoue, Satohiro Masuda, Yoichi Nakanishi, Isamu Okamoto, Safety and efficacy of PD-1 inhibitors in non–small cell lung cancer patients positive for antinuclear antibodies, Lung Cancer, 10.1016/j.lungcan.2019.01.014, 130, 5-9, 2019.04, Objectives: To examine the possible effects of antinuclear antibodies (ANA) on the safety and efficacy of programmed cell death–1 (PD-1) inhibitors in patients with advanced non–small cell lung cancer (NSCLC). Patients and methods: Clinical data including ANA status were reviewed retrospectively for patients with advanced NSCLC who received monotherapy with a PD-1 inhibitor. Results: Of the 83 patients analyzed, 18 (21.7%) were positive for ANA. The incidence of immune-related adverse events (irAEs) did not differ significantly between patients with ANA (6/18, 33.3%) and those negative for ANA (21/65, 32.3%), although it tended to increase as the ANA titer increased. Progression-free survival (2.9 versus 3.8 months, p = 0.03) and overall survival (11.6 versus 15.8 months, p = 0.03) were significantly shorter in patients positive for ANA than in those without ANA. Conclusion: PD-1 inhibitors can be administered safely in advanced NSCLC patients positive for ANA without obvious exacerbation of autoimmune disease, although patients with a high titer of such antibodies may warrant close monitoring. However, the presence of ANA might be associated with a poor outcome of such treatment..
9. Naoki Kubo, Taishi Harada, Yoshimasa Shiraishi, Kaname Nosaki, Noriaki Nakagaki, Masafumi Takeshita, Hiroshi Ouchi, Eiji Iwama, Kentaro Tanaka, Isamu Okamoto, Hiroyuki Sasaki, Yoichi Nakanishi, Identification of genomic alterations acquired during treatment with EGFR-TKIs in non-small cell lung cancer, Anticancer research, 10.21873/anticanres.13162, 39, 2, 671-677, 2019.02, Background/Aim: Patients with non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) eventually develop resistance to these drugs. Although various mechanisms of such resistance have been identified, the mechanism in many cases remains unknown. Materials and Methods: Whole-exome sequencing was performed for tumor tissue from 15 patients with NSCLC who developed EGFR-TKI resistance. Tumor specimens obtained before EGFR-TKI treatment were also analyzed for four patients and normal white blood cell samples for six patients in order to detect genomic alterations that occurred during treatment. Results: The mutational signature and mutational load acquired during EGFR-TKI treatment varied among patients, with common EGFR-TKI resistance mechanisms including the T790M secondary mutation of EGFR and MET amplification being acquired together with many other genomic alterations. Our results provide insight into the mutational landscape acquired during the development of EGFR-TKI resistance in NSCLC..
10. Satoshi Anai, Eiji Iwama, Yasuto Yoneshima, Kohei Otsubo, Kentaro Tanaka, Yoichi Nakanishi, Isamu Okamoto, Association of nephrotoxicity during platinum-etoposide doublet therapy with UGT1A1 polymorphisms in small cell lung cancer patients, Lung Cancer, 10.1016/j.lungcan.2018.11.002, 126, 156-161, 2018.12, Objectives: Etoposide is a key agent in the treatment of small cell lung cancer (SCLC). Uridine diphosphate (UDP)–glucuronosyltransferase 1A1 (UGT1A1) is thought to be largely responsible for the glucuronidation of etoposide as well as that of irinotecan, suggesting that polymorphisms of UGT1A1 might be predictive of etoposide toxicity. We therefore examined the relation between UGT1A1 polymorphisms and toxicity profile during platinum-etoposide doublet therapy in SCLC patients. Materials and Methods: SCLC patients who underwent platinum-etoposide doublet therapy and molecular testing for UGT1A1 genotype were reviewed for the occurrence of adverse events during treatment. Results: A total of 41 SCLC patients received platinum-etoposide doublet therapy and were genotyped for UGT1A1*6 and UGT1A1*28 alleles. These alleles were detected in 15 (36.6%) patients, with the genotypes of *6/– *6/*6, *28/– *28/*28, or *6/*28 being observed in 9 (22.0%), 2 (4.9%), 2 (4.9%), 1 (2.4%), and 1 (2.4%) patients, respectively. The presence of these alleles was significantly associated with an increase in serum creatinine concentration of grade ≥2 (incidence of 66.7% for patients with the alleles versus 11.5% for those without, P < 0.001). Multivariate analysis also showed that these UGT1A1 alleles were significantly associated with therapy-induced nephrotoxicity (odds ratio of 19.30, 95% confidence interval of 2.50–149.00, P < 0.005). Although the differences did not achieve statistical significance, the incidence of other severe toxicities including febrile neutropenia was also slightly higher in patients with the UGT1A1*6 or UGT1A1*28 alleles than in those without them. Conclusion: Our results reveal an association between UGT1A1 polymorphisms and toxicity of platinum-etoposide doublet therapy in SCLC patients, suggesting that close monitoring for toxicity, especially nephrotoxicity, is warranted for patients with such variant alleles receiving this treatment..
11. Maako Ide, Kentaro Tanaka, Shunya Sunami, Tatsuma Asoh, Takashige Maeyama, Nobuko Tsuruta, Yoichi Nakanishi, Isamu Okamoto, Durable response to nivolumab in a lung adenocarcinoma patient with idiopathic pulmonary fibrosis, Thoracic Cancer, 10.1111/1759-7714.12853, 9, 11, 1519-1521, 2018.11, The efficacy and safety of immune-checkpoint inhibitors in non-small cell lung cancer patients with idiopathic pulmonary fibrosis (IPF) remain unknown. Herein, we describe the case of a 62-year-old man with multiple pleural tumors and carcinomatous pleurisy. High-resolution computed tomography indicated usual interstitial pneumonia, and a respiratory function test revealed a restrictive disorder and decreased diffusion capacity. He was diagnosed with lung adenocarcinoma and IPF. After failure of initial chemotherapy, he was treated with nivolumab and achieved a complete response without any sign of exacerbation of IPF. The response to nivolumab has persisted for > 1 year. This is the first report of a non-small cell lung cancer patient with IPF who has been treated with immune-checkpoint inhibitors for such a long period and achieved a sustained response..
12. Shinichi Kimura, Kentaro Tanaka, Taishi Harada, Renpeng Liu, Daisuke Shibahara, Yuko Kawano, Yoichi Nakanishi, Isamu Okamoto, Sensitivity of epidermal growth factor receptor with single or double uncommon mutations to afatinib confirmed by a visual assay, Cancer Science, 10.1111/cas.13787, 109, 11, 3657-3661, 2018.11, Patients with non-small cell lung cancer (NSCLC) harboring common mutations of the epidermal growth factor receptor (EGFR) are sensitive to EGFR-tyrosine kinase inhibitors (TKI). Although forms of EGFR harboring single uncommon mutations such as G719X or L861Q are thought to be less sensitive to EGFR-TKI, the efficacy of these drugs in patients with double uncommon mutations has remained unclear. We here present an NSCLC patient found to be positive for double uncommon EGFR mutations (G719X and L861Q) by clinical genomic sequencing analysis of a pleural effusion specimen who showed a durable response to the EGFR-TKI afatinib. The sensitivity of EGFR with single or double uncommon mutations to afatinib and the EGFR-TKI erlotinib was also evaluated in vitro with a visual assay based on HEK293 cells transiently transfected with expression plasmids for yellow fluorescent protein (YFP)-tagged fragments of the EGFR intracellular domain (ICD). Whereas forms of EGFR with double uncommon mutations were more sensitive to erlotinib than were those with single uncommon mutations, those with single or double uncommon mutations were similarly sensitive to afatinib, consistent with the patient's clinical outcome. Our data support the notion that afatinib is the most suitable EGFR-TKI for NSCLC harboring uncommon mutations of EGFR. Furthermore, the YFP-EGFR-ICD assay is potentially applicable to prediction of EGFR-TKI efficacy in patients with such mutations..
13. Kentaro Tanaka, Toyoshi Yanagihara, Yuki Ikematsu, Hiroyuki Inoue, keiichi ota, Eiji Kashiwagi, Kunihiro Suzuki, Naoki Hamada, ario takeuchi, Katsunori Tatsugami, Masatoshi Eto, Kayo Ijichi, Yoshinao Oda, Kohei Otsubo, Yasuto Yoneshima, Eiji Iwama, Yoichi Nakanishi, Isamu Okamoto, Detection of identical T cell clones in peritumoral pleural effusion and pneumonitis lesions in a cancer patient during immune-checkpoint blockade, Oncotarget, 10.18632/oncotarget.25743, 9, 55, 30587-30593, 2018.07, Although immune-related adverse events (irAEs) of treatment with immunecheckpoint inhibitors may be due to cellular immunity mediated by T lymphocytes, their pathogenesis has remained unknown. Here we collected bronchoalveolar lavage fluid (BALF) from a cancer patient with nivolumab-induced pneumonitis and isolated mononuclear cells for next-generation sequencing of the complementarity-determining region of the T cell receptor (TCR) β chain. Mononuclear cells in peritumoral pleural effusion isolated from the patient were similarly analyzed, and the results obtained for the two specimens were compared. A substantial number of TCRβ clones in BALF were also identified among lymphocytes in the peritumoral pleural effusion. Such a correlation was not apparent between TCRβ clones in BALF and those in peripheral blood. Moreover, many tumor-associated clones with a read frequency of =0.10% were also present in BALF. Our data suggest that irAEs might be induced by drugactivated lymphocytes originating from tumor tissue. Deep sequencing will thus be indispensable for investigations of the immune-based pathogenesis of, and the development of optimal treatments for, irAEs..
14. Daisuke Shibahara, Kentaro Tanaka, Eiji Iwama, Naoki Kubo, keiichi ota, Koichi Azuma, Taishi Harada, Jiro Fujita, Yoichi Nakanishi, Isamu Okamoto, Intrinsic and Extrinsic Regulation of PD-L2 Expression in Oncogene-Driven Non–Small Cell Lung Cancer, Journal of Thoracic Oncology, 10.1016/j.jtho.2018.03.012, 13, 7, 926-937, 2018.07, Introduction: The interaction of programmed cell death ligand 2 (PD-L2) with programmed cell death 1 is implicated in tumor immune escape. The regulation of PD-L2 expression in tumor cells has remained unclear, however. We here examined intrinsic and extrinsic regulation of PD-L2 expression in NSCLC. Methods: PD-L2 expression was evaluated by reverse transcription and real-time polymerase chain reaction analysis and by flow cytometry. Results: BEAS-2B cells stably expressing an activated mutant form of EGFR or the echinoderm microtubule associated protein like 4 (EML4)–ALK receptor tyrosine kinase fusion oncoprotein manifested increased expression of PD-L2 at both the mRNA and protein levels. Furthermore, treatment of NSCLC cell lines that harbor such driver oncogenes with corresponding EGFR or ALK tyrosine kinase inhibitors or depletion of EGFR or ALK by small interfering RNA transfection suppressed expression of PD-L2, demonstrating that activating EGFR mutations or echinoderm microtubule associated protein like 4 gene (EML4)–ALK receptor tyrosine kinase gene (ALK) fusion intrinsically induce PD-L2 expression. We also found that interferon gamma (IFN-γ) extrinsically induced expression of PD-L2 through signal transducer and activator of transcription 1 signaling in NSCLC cells. Oncogene-driven expression of PD-L2 in NSCLC cells was inhibited by knockdown of the transcription factors signal transducer and activator of transcription 3 (STAT3) or c-FOS. IFN-γ also activated STAT3 and c-FOS, suggesting that these proteins may also contribute to the extrinsic induction of PD-L2 expression. Conclusions: Expression of PD-L2 is induced intrinsically by activating EGFR mutations or EML4-ALK fusion and extrinsically by IFN-γ, with STAT3 and c-FOS possibly contributing to both intrinsic and extrinsic pathways. Our results thus provide insight into the complexity of tumor immune escape in NSCLC..
15. Shinya Tanaka, Yu Jiang, Gustavo J. Martinez, Kentaro Tanaka, Xiaowei Yan, Tomohiro Kurosaki, Vesa Kaartinen, Xin Hua Feng, Qiang Tian, Xiaohu Wang, Chen Dong, Trim33 mediates the proinflammatory function of Th17 cells, Journal of Experimental Medicine, 10.1084/jem.20170779, 215, 7, 1853-1868, 2018.07, Transforming growth factor–β (TGF-β) regulates reciprocal regulatory T cell (T reg) and T helper 17 (Th17) differentiation, the underlying mechanism of which is still not understood. Here, we report that tripartite motif-containing 33 (Trim33), a modulator of TGF-β signaling that associates with Smad2, regulates the proinflammatory function of Th17 cells. Trim33 deficiency in T cells ameliorated an autoimmune disease in vivo. Trim33 was required for induction in vitro of Th17, but not T reg cells. Moreover, Smad4 and Trim33 play contrasting roles in the regulation of IL-10 expression; loss of Trim33 enhanced IL-10 production. Furthermore, Trim33 was recruited to the Il17a and Il10 gene loci, dependent on Smad2, and mediated their chromatin remodeling during Th17 differentiation. Trim33 thus promotes the proinflammatory function of Th17 cells by inducing IL-17 and suppressing IL-10 expression..
16. Shinichi Kimura, Taishi Harada, Kayo Ijichi, Kentaro Tanaka, Renpeng Liu, Daisuke Shibahara, Yuko Kawano, Kohei Otsubo, Yasuto Yoneshima, Eiji Iwama, Yoichi Nakanishi, Isamu Okamoto, Expression of brain-derived neurotrophic factor and its receptor TrkB is associated with poor prognosis and a malignant phenotype in small cell lung cancer, Lung Cancer, 10.1016/j.lungcan.2018.04.005, 120, 98-107, 2018.06, Objectives: TrkB is a receptor for brain-derived neurotrophic factor (BDNF) and is highly expressed in various cancers, with BDNF-TrkB signaling having been implicated in tumor progression and metastasis. The role of the BDNF-TrkB system in small cell lung cancer (SCLC), a neuroendocrine cancer, has remained unclear, however. We examined BDNF and TrkB expression in SCLC patients as well as the function of BDNF-TrkB signaling in SCLC cell lines. Materials and methods: BDNF and TrkB expression in tumor specimens of 58 SCLC patients and 20 non–small cell lung cancer (NSCLC) patients was examined by immunohistochemistry and was scored on the basis of the distribution and intensity of staining. TrkB-overexpressing SCLC (SBC5 TrkB ) cells were established by retrovirus transduction and were examined for the effects of BDNF on intracellular signaling, cell proliferation, and cell migration in vitro. Results: The staining score for TrkB in NSCLC and SCLC specimens was 2.80 ± 0.19 and 3.60 ± 0.15, respectively, whereas that for BDNF was 1.95 ± 0.32 and 2.76 ± 0.14, respectively. High levels of both TrkB and BDNF expression in SCLC tumors were significantly associated with poor overall survival in multivariate analysis (hazard ratio = 1.821, P = 0.036). BDNF activated AKT and ERK signaling pathways in and promoted the migration of SBC5 TrkB cells, and these effects were attenuated by the pan-Trk inhibitor GNF-5837. GNF-5837 also inhibited the proliferation of SBC5 TrkB cells in the presence of BDNF. Conclusion: Coexpression of BDNF and TrkB was associated with poor prognosis in SCLC patients, and BDNF promoted the migration of TrkB-overexpressing SCLC cells. TrkB is thus a potential therapeutic target for SCLC..
17. Kentaro Tanaka, Gustavo J. Martinez, Xiaowei Yan, Weiwen Long, Kenji Ichiyama, Xinxin Chi, Byung Seok Kim, Joseph M. Reynolds, Yeonseok Chung, Shinya Tanaka, Lan Liao, Yoichi Nakanishi, Akihiko Yoshimura, Pan Zheng, Xiaohu Wang, Qiang Tian, Jianming Xu, Bert W. O'Malley, Chen Dong, Regulation of Pathogenic T Helper 17 Cell Differentiation by Steroid Receptor Coactivator-3, Cell Reports, 10.1016/j.celrep.2018.04.088, 23, 8, 2318-2329, 2018.05, T helper 17 (Th17) cell development is programmed by the orphan nuclear receptor RORγt, but the underlying mechanism is not well understood. Nuclear receptor-mediated transcriptional activation depends on coactivators. Here, we show that steroid receptor coactivator-3 (SRC-3) critically regulates Th17 cell differentiation. Reduced incidence of experimental autoimmune encephalitis (EAE) associated with decreased Th17 cell generation in vivo was observed in mice with SRC-3 deletion specifically in T cells. In vitro, SRC-3 deficiency did not affect TGF-β/IL-6-induced Th17 cell generation but severely impaired pathogenic Th17 differentiation induced by IL-1/IL-6/IL-23. Microarray analysis revealed that SRC-3 not only regulates IL-17A but also IL-1R1 expression. SRC-3 bound to Il17a and Il1r1 loci in a RORγt-dependent manner and was required for recruitment of the p300 acetyltransferase. Thus, SRC-3 is critical for RORγt-dependent gene expression in Th17 cell-driven autoimmune diseases. The unique transcriptional programs in IL-1-induced inflammatory Th17 cells have remained unclear. Tanaka et al. demonstrate that SRC-3 in CD4+ T helper cells functions as a specific coactivator of RORγt, a master transcription factor of Th17 cells, by regulating IL-1-IL1R1 signaling..
18. Yasuto Yoneshima, Kayo Ijichi, Satoshi Anai, keiichi ota, Kohei Otsubo, Eiji Iwama, Kentaro Tanaka, Yoshinao Oda, Yoichi Nakanishi, Isamu Okamoto, PD-L1 expression in lung adenocarcinoma harboring EGFR mutations or ALK rearrangements, Lung Cancer, 10.1016/j.lungcan.2018.01.024, 118, 36-40, 2018.04, Objectives: Expression of programmed cell death–ligand 1 (PD-L1) has been associated with clinical outcome of programmed cell death–1 (PD-1) pathway blockade in non–small cell lung cancer (NSCLC). The PD-L1 IHC 22C3 pharmDx assay, the only companion diagnostic for pembrolizumab therapy, has revealed that ∼30% of all NSCLCs express PD-L1 at a high level. The frequency of high PD-L1 expression in NSCLCs with known driver oncogenes has remained unclear, however. Materials and methods: We retrospectively evaluated PD-L1 expression with the 22C3 assay in tumor tissue of 80 lung adenocarcinoma patients including 71 with EGFR mutations and 9 with ALK rearrangements, all of whom were treated with corresponding tyrosine kinase inhibitors (TKIs). Results: Of the 80 tumors analyzed, 26 (32.5%) had a PD-L1 tumor proportion score (TPS) of 1%–49% and 9 (11.3%) had a PD-L1 TPS of ≥50%; 35 (43.8%) thus had a PD-L1 TPS of ≥1%. Of the 71 tumors with EGFR mutations, 23 (32.4%) had a PD-L1 TPS of 1%–49% and 7 (9.9%) had a PD-L1 TPS of ≥50%. A PD-L1 TPS of ≥1% was not associated with any clinical characteristic examined. Progression-free survival on initial TKI treatment was significantly poorer for patients with a PD-L1 TPS of ≥1% than for those with a PD-L1 TPS of <1% (p =.016). Conclusions: A subset of patients with EGFR mutations or ALK rearrangements had a PD-L1 TPS of ≥50%. Prospective studies are thus warranted to examine the efficacy of PD-1/PD-L1 inhibitors in such patients..
19. Yanagihara T, Ikematsu Y, Kato K, Yonekawa A, Ideishi S, Tochigi T, Sugio T, Miyawaki K, Tanaka K, Harada E, Hamada N, Nakanishi Y., Expression of PD-1 and PD-L1 on cytotoxic T lymphocytes and immune deficiency in a patient with adult T cell leukemia/lymphoma., Annals of Hematology, 2018.02.
20. Toyoshi Yanagihara, Yuki Ikematsu, Koji Kato, Akiko Yonekawa, Satoko Ideishi, Taro Tochigi, Takeshi Sugio, Kohta Miyawaki, Kentaro Tanaka, Eiji Harada, Naoki Hamada, Yoichi Nakanishi, Expression of PD-1 and PD-L1 on cytotoxic T lymphocytes and immune deficiency in a patient with adult T cell leukemia/lymphoma, Annals of Hematology, 10.1007/s00277-017-3146-z, 97, 2, 359-360, 2018.02.
21. Kentaro Tanaka, Kumiko Isse, Tomomichi Fujihira, Mitsuhiro Takenoyama, Laura Saunders, Sheila Bheddah, Yoichi Nakanishi, Isamu Okamoto, Prevalence of Delta-like protein 3 expression in patients with small cell lung cancer, Lung Cancer, 10.1016/j.lungcan.2017.11.018, 115, 116-120, 2018.01, Objectives Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC) positive for this protein. However, the prevalence of DLL3 expression and its association with patient ethnicity and other characteristics have remained unclear. Materiais and methods Tumor samples from 63 patients with SCLC were subjected to immunohistochemical staining for DLL3. The relation of patient characteristics including sex, age, disease stage, and smoking history to DLL3 expression status was analyzed. Results and conlusions Fifty-two patients (83%) were positive for DLL3 expression, with 20 patients (32%) being positive in at least 50% of cancer cells (DLL3-high). DLL3 expression was not associated with any of the patient characteristics examined. In addition, overall survival did not differ between DLL3-high and DLL3-low patients. Our results reveal that DLL3 is expressed in tumor specimens from most patients with SCLC, and they should inform the undertaking of clinical trials of Rova-T including an ongoing phase I study (NCT03086239) in Japan as well as global phase III trials (NCT03061812 and NCT03033511)..
22. Kawano Y, Iwama E, Tsuchihashi K, Shibahara D, Harada T, Tanaka K., Nagano O, Saya H, Nakanishi Y & Okamoto I., CD44 variant–dependent regulation of redox balance in EGFR mutation–positive non–small cell lung cancer: A target for treatment, Lung Cancer, 2017.11.
23. Kim BS, Lu H, Ichiyama K, Chen X, Zhang YB, Mistry NA, Tanaka K, Lee YH, Nurieva R, Zhang L, Yang X, Chung Y, Jin W, Chang SH, Dong C., Generation of RORγt+ Antigen-Specific T Regulatory 17 Cells from Foxp3+ Precursors in Autoimmunity., Cell Reports, 2017.10.
24. Ikematsu Y, Yoneshima Y, Ijichi K, Tanaka K, Harada T, Oda Y, Nakanishi Y, Okamoto I., Marked response to pembrolizumab in a patient with pulmonary pleomorphic carcinoma highly positive for PD-L1., Lung Cancer, 2017.10.
25. Byung Seok Kim, Huiping Lu, Kenji Ichiyama, Xiang Chen, Yi Bing Zhang, Nipun A. Mistry, Kentaro Tanaka, Young hee Lee, Roza Nurieva, Li Zhang, Xuexian Yang, Yeonseok Chung, Wei Jin, Seon Hee Chang, Chen Dong, Generation of RORγt
Antigen-Specific T Regulatory 17 Cells from Foxp3
Precursors in Autoimmunity, Cell Reports, 10.1016/j.celrep.2017.09.021, 21, 1, 195-207, 2017.10, Th17 cells are potent mediators in autoimmune diseases, and RORγt is required for their development. Recent studies have shown that RORγt
Treg cells in the gut regulate intestinal inflammation by inhibiting effector T cell function. In the current study, we report that RORγt
Treg cells were also found in lymph nodes following immunization. Not only distinct from intestinal RORγt
Treg cells in their transcriptomes, peripheral RORγt
Treg cells were derived from Foxp3
thymic Treg cells in an antigen-specific manner. Development of these RORγt
Treg cells, coined T regulatory 17 (Tr17) cells, depended on IL-6/Stat3 signaling. Tr17 cells showed suppressive activity against antigen-specific effector T cells in vitro. In addition, Tr17 cells efficiently inhibited myelin-specific Th17-cell-mediated CNS auto-inflammation in a passive EAE model. Collectively, our study demonstrates that Tr17 cells are effector Treg cells that potentially restrict autoimmunity. Kim et al. find that RORγt
T regulatory 17 (Tr17) cells are induced in lymph nodes after immunization. Tr17 cells are generated from thymic Treg cells in an antigen-specific manner through Stat3 signaling. Their data suggest that Tr17 cells represent antigen-specific effector Treg cells that can regulate Th17-cell-dependent autoimmunity..
26. Yuki Ikematsu, Yasuto Yoneshima, Kayo Ijichi, Kentaro Tanaka, Taishi Harada, Yoshinao Oda, Yoichi Nakanishi, Isamu Okamoto, Marked response to pembrolizumab in a patient with pulmonary pleomorphic carcinoma highly positive for PD-L1, Lung Cancer, 10.1016/j.lungcan.2017.07.020, 112, 230-231, 2017.10.
27. Yanagihara T, Tanaka K, Ota K, Kashiwagi E, Takeuchi A, Tatsugami K, Eto M, Nakanishi Y, Okamoto I., Tumor-infiltrating lymphocyte-mediated pleuritis followed by marked shrinkage of metastatic kidney cancer of the chest wall during nivolumab treatment., Annals of Oncology, 2017.08.
28. Toyoshi Yanagihara, Kentaro Tanaka, keiichi ota, Eiji Kashiwagi, ario takeuchi, Katsunori Tatsugami, Masatoshi Eto, Yoichi Nakanishi, Isamu Okamoto, Tumor-infiltrating lymphocyte-mediated pleuritis followed by marked shrinkage of metastatic kidney cancer of the chest wall during nivolumab treatment, Annals of Oncology, 10.1093/annonc/mdx214, 28, 8, 2038-2039, 2017.08.
29. Tanaka K, Nosaki K, Otsubo K, Azuma K, Sakata S, Ouchi H, Morinaga R, Wataya H, Fujii A, Nakagaki N, Tsuruta N, Takeshita M, Iwama E, Harada T, Nakanishi Y, Okamoto I., Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naïve patients with non-small cell lung cancer harboring EGFR mutations., Oncotarget, 2017.07.
30. Ota K, Harada T, Otsubo K, Fujii A, Tsuchiya Y, Tanaka K, Okamoto I, Nakanishi Y., Visualization and quantitation of epidermal growth factor receptor homodimerization and activation with a proximity ligation assay., Oncotarget, 2017.07.
31. Hidaka N, Iwama E, Kubo N, Harada T, Miyawaki K, Tanaka K, Okamoto I, Baba E, Akashi K, Sasaki H, Nakanishi Y., Most T790M mutations are present on the same EGFR allele as activating mutations in patients with non-small cell lung cancer., Lung Cancer, 2017.06.
32. Noriko Hidaka, Eiji Iwama, Naoki Kubo, Taishi Harada, Kohta Miyawaki, Kentaro Tanaka, Isamu Okamoto, Eishi Baba, Koichi Akashi, Hiroyuki Sasaki, Yoichi Nakanishi, Most T790M mutations are present on the same EGFR allele as activating mutations in patients with non–small cell lung cancer, Lung Cancer, 10.1016/j.lungcan.2017.02.019, 108, 75-82, 2017.06, Objectives The T790M and C797S mutations of the epidermal growth factor receptor gene (EGFR) confer resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), respectively, in patients with non–small cell lung cancer (NSCLC) harboring activating mutations of EGFR. C797S has been identified in cis or in trans with T790M in tumor specimens from patients who experienced treatment failure with first- and third-generation EGFR-TKIs. The allelic relation between T790M and activating mutations of EGFR has not been well characterized, however. We have now developed a digital polymerase chain reaction (dPCR)–based method for determination of the allelic relation between two types of EGFR mutation (T790M and either C797S or an activating mutation). Materials and Methods Seven clinical NSCLC specimens and two NSCLC cell lines harboring both an activating mutation and T790M were analyzed with this new method to identify the allelic relation between these EGFR mutations. Results The median ratio of the number of alleles positive for both an activating mutation and T790M to the number of T790M-positive alleles was 97.1% (range, 90.0–100%). Confirmatory analysis by next-generation sequencing yielded a corresponding value of 96.7% (range, 89.1–99.5%). Our dPCR method thus reliably identifies the allelic relation between two EGFR mutations in a quantitative manner. Conclusions Almost all T790M mutations were detected in cis with activating mutations of EGFR regardless of the de novo or acquired status of T790M, with cancer cells harboring T790M and activating mutations on the same allele appearing to be selected and enriched during EGFR-TKI treatment..
33. Anupama Sahoo, Andrei Alekseev, Kentaro Tanaka, Lidiya Obertas, Beatrisa Lerman, Cara Haymaker, Karen Clise-Dwyer, John S. McMurray, Roza Nurieva, Batf is important for IL-4 expression in T follicular helper cells, Nature communications, 10.1038/ncomms8997, 6, 2015.08, Apart from T helper (Th)-2 cells, T follicular helper (Tfh) cells are a major class of IL-4-producing T cells, required for regulation of type 2 humoral immunity; however, transcriptional control of IL-4 production in Tfh cells remains mainly unknown. Here, we show that the basic leucine zipper transcription factor ATF-like, Batf is important for IL-4 expression in Tfh cells rather than in canonical Th2 cells. Functionally, Batf in cooperation with interferon regulatory factor (IRF) 4 along with Stat3 and Stat6 trigger IL-4 production in Tfh cells by directly binding to and activation of the CNS2 region in the IL-4 locus. In addition, Batf-to-c-Maf signalling is an important determinant of IL-4 expression in Tfh cells. Batf deficiency impairs the generation of IL-4-producing Tfh cells that results in protection against allergic asthma. Our results thus indicate a positive role of Batf in promoting the generation of pro-allergic IL-4-producing Tfh cells..
34. Shinya Tanaka, Kentaro Tanaka, Fay Magnusson, Yeonseok Chung, Gustavo J. Martinez, Yi Hong Wang, Roza I. Nurieva, Tomohiro Kurosaki, Chen Dong, CCAAT/enhancer-binding protein α negatively regulates IFN-γ expression in T cells, Journal of Immunology, 10.4049/jimmunol.1303422, 193, 12, 6152-6160, 2014.01, Humoral immunity, including Ab switching and somatic hypermutation, is critically regulated by CD4+ T cells. T follicular helper (Tfh) cells have been recently shown to be a distinct T cell subset important in germinal center reactions. The transcriptional regulation of Tfh cell development and function has not been well understood. In this study, we report that C/EBPα, a basic region/leucine zipper transcription factor, is highly expressed in Tfh cells. Cebpa-deficient CD4+ T cells exhibit enhanced IFN-γ expression in vitro and in vivo. T cell-specific Cebpa knockout mice, although not defective in Tfh cell generation, produce significantly increased levels of IgG2a/b and IgG3 following immunization with a protein Ag. Moreover, C/EBPα binds to the Ifng gene and inhibits T-bet-driven Ifng transcription in a DNA binding-dependent manner. Our study thus demonstrates that C/EBPα restricts IFN-γ expression in T cells to allow proper class switching by B cells..
35. Shuo Wang, Koichi Takayama, Kentaro Tanaka, Masafumi Takeshita, Noriaki Nakagaki, Kayo Ijichi, Heyan Li, Yoichi Nakanishi, Nicotine induces resistance to epidermal growth factor receptor tyrosine kinase inhibitor by α1 nicotinic acetylcholine receptor-mediated activation in PC9 cells, Journal of Thoracic Oncology, 10.1097/JTO.0b013e31828b51d4, 8, 6, 719-725, 2013.01, Introduction: Nicotine, the major component among the 4000 identified chemicals in cigarette smoke, binds to nicotinic acetylcholine receptors (nAChRs) on non-small-cell lung cancer (NSCLC) cells and regulates cellular proliferation by activating mitogen-activated protein kinases [AQ: MAPK has been expanded to mitogen-activated protein kinases. Please approve.]and PI3K/Akt pathways. In patients with smoking-related lung cancer who continue smoking, the anticancer effect of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is weaker than that in nonsmokers; however, the precise reason for this difference remains unclear. We investigated the role of α1 nAChR subunit in this phenomenon. Methods: We screened for α1 nAChR mRNA in three NSCLC cell lines and analyzed the protein in resected primary NSCLC tissues. We used Western blot and RNA interference (siRNA) methodology to confirm the results. Results: We determined that α1 nAChR plays an essential role in nicotine-induced cell signaling and nicotine-induced resistance to EGFR-TKI. In addition, we showed that silencing of α1 nAChR subunit in NSCLC may suppress the nicotine-induced resistance to EGFR-TKI. Conclusions: These results further implicate nicotine in lung carcinogenesis, and suggest that α1 nAChR may be a biomarker for EGFR-TKI treatment and also a personalizing target molecule for patients with smoking-related lung cancer..
36. Koichiro Matsumoto, Yukari Asai, Satoru Fukuyama, Keiko Kan-o, Yuko Matsunaga, Naotaka Noda, Hiroko Kitajima, Kentaro Tanaka, Yoichi Nakanishi, Hiromasa Inoue, IL-6 induced by double-stranded RNA augments allergic inflammation via suppression of Foxp3+T-cell/IL-10 axis, American Journal of Respiratory Cell and Molecular Biology, 10.1165/rcmb.2010-0479OC, 46, 6, 740-747, 2012.06, Activation of innate immunity against viruses in the respiratory tracts affects the development of asthma. Most respiratory viruses generate double-stranded (ds)RNA during their replication. We recently showed that a low-dose administration of polyinosinic polycytidylic acid (poly IC), a mimetic of viral dsRNA, during allergen sensitization augments airway eosinophilia and hyperresponsiveness in mice via enhanced production of IL-13 from T cells. However, a phenotype of asthma under severer load of dsRNA remains unknown. D-galactosamine (D-GalN) is known as a strong sensitizer of poly IC. Mice weretreated with poly IC plus D-GalN during allergen sensitization. A sublethal dose of poly IC/D-GalN augmented airway eosinophilia and CD4+ T-cell accumulation in the lungs but not airway hyperresponsiveness. The augmented inflammation was associated with decreased IL-10 in the bronchoalveolar lavage fluid and decreased Foxp3+ regulatory T cells in the lungs. Serum IL-6 was prominently higher in the mice treated with poly IC/D-GalN than in that with poly IC alone or D-GalN alone. Poly IC/D-GalN did not affect IL-17-producing T cells in the lungs. Poly IC/D-GalN failed to augment airway eosinophilia after anti-IL-10 receptor monoclonal antibody treatment during allergen challenge. Finally, anti-IL-6 receptor monoclonal antibody treatment before poly IC/D-GalN completely prevented the decrease of IL-10 and Foxp3 + regulatory T cells and the augmentation of airway inflammation. These results indicate that enhanced production of IL-6 by poly IC/D-GalN induces the augmentation of allergic inflammation via suppression of Foxp3 + regulatory T-cell/IL-10 axis. IL-6 may be a target for preventing asthma augmentation related to severevirus infection..
37. Yumiko Abe, Kentaro Tanaka, Koichiro Matsumoto, Koichi Takayama, Hiroyuki Inoue, Miiru Izumi, Hiromasa Inoue, Yoichi Nakanishi, [A case of non-small cell lung cancer with hemodialysis which responded to docetaxel monotherapy]., Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society, 48, 10, 769-773, 2010.01, A 56-year-old man receiving hemodialysis treatment was hospitalized for examination of a mass in the right middle lobe. Chest computed tomography showed a right hilar mass shadow accompanied by pleural effusion. Non-small cell lung cancer (NSCLC) was diagnosed by cytological examination of the pleural effusion. No epidermal growth factor receptor (EGFR) mutation was found. He was treated with 6 courses of docetaxel as first-line chemotherapy. Docetaxel was administered on the same day as hemodialysis. Adverse events, including hematotoxicity, were managed safely and no delay in administration occurred. This chemotherapy resulted in a partial response. Because docetaxel is metabolized in the liver and does not affect renal function, it can be administered as a standard regimen. This suggests that docetaxel monotherapy is an efficient therapy for non-small cell lung cancer patients receiving hemodialysis..
38. Kyoko Kudo, Miiru Izumi, Koichi Takayama, Satoru Fukuyama, Kentaro Tanaka, Yoichi Nakanishi, Paraneoplastic brainstem encephalitis and subacute sensory neuropathy presenting various neurological symptoms associated with small cell lung cancer, Japanese Journal of Lung Cancer, 10.2482/haigan.49.852, 49, 6, 852-856, 2009.10, Background. Paraneoplastic brainstem encephalitis and subacute sensory neuropathy are included in paraneoplastic neurological syndrome (PNS) and are rarely accompanied by small cell lung cancer. PNS is often difficult to diagnose or to treat them. Case. A 71 year-old man presented with syncope, diplopia, blepharoptosis and dysphagia and was admitted to our hospital. Brain MRI was normal. Chest CT showed mediastinal lymphadenopathy. The lymph node biopsy yielded a diagnosis of small cell lung cancer (cT4N2M0, stage IIIB). And as for the neurological symptoms, the presence of a serum anti-Hu antibody supported the diagnosis of paraneoplastic brainstem encephalitis and subacute sensory neuropathy. Platinum-based chemotherapy resulted in partial response but the neurological symptoms deteriorated. Conclusion. We reported a case of paraneoplastic brainstem encephalitis and subacute sensory neuropathy accompanied by small cell lung cancer. There are vari-ous types of paraneoplastic neurological syndrome, and further studies for the treatment of each neurological symptom are required..
39. Satoru Fukuyama, Takako Nakano, Takafumi Matsumoto, Brian G.G. Oliver, Janette K. Burgess, Atsushi Moriwaki, Kentaro Tanaka, Masato Kubo, Tomoaki Hoshino, Hiroyuki Tanaka, Andrew N.J. McKenzie, Koichiro Matsumoto, Hisamichi Aizawa, Yoichi Nakanishi, Akihiko Yoshimura, Judith L. Black, Hiromasa Inoue, Pulmonary suppressor of cytokine signaling-1 induced by IL-13 regulates allergic asthma phenotype, American Journal of Respiratory and Critical Care Medicine, 10.1164/rccm.200806-992OC, 179, 11, 992-998, 2009.06, Rationale: Th2 cytokines play an important role in allergic diseases. These cytokines activate signal transduction pathways, including Janus kinase/signal transducer and activator of transcription (STAT) signaling. Although the suppressor of cytokine signaling (SOCS) family protein, a negative regulator of the Janus kinase/STAT signaling pathway, contributes to helper T cell differentiation during immune responses, the role of SOCS proteins within the structural cells of a target organ has not been clarified in allergy. Objectives: To study the local function of SOCS in the development of asthma. Methods: We used mouse models of IL-13- and ovalbumin (OVA)-induced allergic airway disease. Airway smooth muscle cells were cultured from patients with asthma. Measurements and Main Results: The administration of IL-13 induced not only airway responses but also SOCS1 expression at the local inflammatory site. The up-regulated SOCS1 markedly suppressed IL-13-dependent STAT6 activation and eotaxin expression and subsequently down-regulated IL-13-induced airway inflammatory responses. The inactivation of SOCS1 induced airway hyperresponsiveness after IL-13 treatment even in hyporesponsive C57BL/6 background mice. In an OVA-induced model of allergic airway disease, allergen exposure up-regulated local SOCS1 expression, and the induction of SOCS1 in the airways attenuated allergen-induced airway responses. Inactivation of IL-13 inhibited SOCS1 induction in a model of allergic airway disease. Interestingly, airway smooth muscle cells from individuals with asthma had impaired upregulation of SOCS1 after IL-13 stimulation. Conclusions: SOCS1 induction by IL-13 in airway structural cells is critical to negatively control allergic airway disease..
40. Li Fan Lu, To Ha Thai, Dinis Pedro Calado, Ashutosh Chaudhry, Masato Kubo, Kentaro Tanaka, Gabriel B. Loeb, Hana Lee, Akihiko Yoshimura, Klaus Rajewsky, Alexander Y. Rudensky, Foxp3-Dependent MicroRNA155 Confers Competitive Fitness to Regulatory T Cells by Targeting SOCS1 Protein, Immunity, 10.1016/j.immuni.2008.11.010, 30, 1, 80-91, 2009.01, Foxp3+ regulatory T (Treg) cells limit pathogenic immune responses to self-antigens and foreign antigens. An essential role for microRNA (miRNA) in the maintenance and function of Treg cells, revealed by the Treg cell-specific Dicer ablation, raised a question as to a specific miRNA contribution. We found that Foxp3 controlled the elevated miR155 expression required for maintaining Treg cell proliferative activity and numbers under nonlymphopenic conditions. Moreover, miR155 deficiency in Treg cells resulted in increased suppressor of cytokine signaling 1 (SOCS1) expression accompanied by impaired activation of signal transducer and activator of transcription 5 (STAT5) transcription factor in response to limiting amounts of interleukin-2. Our studies suggest that Foxp3-dependent regulation of miR155 maintains competitive fitness of Treg cell subsets by targeting SOCS1, and they provide experimental support for a proposed role for miRNAs in ensuring the robustness of cellular phenotypes..
41. Jiro Horino, Minoru Fujimoto, Fumitaka Terabe, Satoshi Serada, Tsuyoshi Takahashi, Yoshihito Soma, Kentaro Tanaka, Takatoshi Chinen, Akihiko Yoshimura, Shintaro Nomura, Ichiro Kawase, Norio Hayashi, Tadamitsu Kishimoto, Tetsuji Naka, Suppressor of cytokine signaling-1 ameliorates dextran sulfate sodium-induced colitis in mice, International Immunology, 10.1093/intimm/dxn033, 20, 6, 753-762, 2008.06, Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract. Although the etiology and pathogenesis of IBD remain unknown, pro-inflammatory cytokines including IFN-γ play an important role in the development of IBD. Suppressor of cytokine signaling-1 (SOCS-1) is a crucial inhibitor of cytokine signaling, particularly of IFN-γ. In this study, we investigated the role of SOCS-1 in the development of murine dextran sulfate sodium (DSS)-induced colitis, a model of colitis resembling human IBD. SOCS-1 heterozygous (SOCS-1+/-) and wild-type (WT) mice were given 3% DSS dissolved in drinking water for 5 days. Activation and expression of signal transducers and activators of transcription (STAT) in colonic tissues were assessed by western blot analysis. The expression of CD4, IFN-γ, IL-4, IL-17 and Forkhead box P3 (Foxp3) in colonic lamina propria lymphocytes was analyzed by flow cytometry and cytokine concentrations in serum were measured. DSS-treated SOCS-1+/- mice developed more severe colitis than DSS-treated WT mice. Enhanced activation of STAT1, a higher ratio of CD4+ IFN-γ+T cells and a lower frequency of Foxp3+ regulatory T (Treg) cells, were observed in the colon of DSS-treated SOCS-1+/- mice compared with DSS-treated WT mice. DSS-treated SOCS-1+/- mice showed higher levels of IFN-γ in sera than did DSS-treated WT mice. Furthermore, T cell-specific SOCS-1-conditional knockout mice developed more severe colitis than control mice after DSS administration. Our findings suggest that SOCS-1, particularly in T cells, prevents the development of DSS-induced colitis in mice by inhibiting IFN-γ/STAT1 signaling and by subsequently regulating Treg cell development..
42. Kentaro Tanaka, Kenji Ichiyama, Masayuki Hashimoto, Hideyuki Yoshida, Tomohito Takimoto, Giichi Takaesu, takehiro torisu, Toshikatsu Hanada, Hideo Yasukawa, Satoru Fukuyama, Hiromasa Inoue, Yoichi Nakanishi, Takashi Kobayashi, Akihiko Yoshimura, Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-γ on STAT3 and Smads, Journal of Immunology, 180, 6, 3746-3756, 2008.03, Suppressor of cytokine signaling 1 (SOCS1) is an important negative regulator for cytokines; however, the role of SOCS1 in Th17 differentiation has not been clarified. We generated T cell-specific SOCS1-deficient mice and found that these mice were extremely resistant to a Th17-dependent autoimmune disease model, experimental autoimmune encephalomyelitis. SOCS1-deficient naive CD4 + T cells were predominantly differentiated into Th1 and poorly into Th17 in vitro. These phenotypes were canceled in IFN-γ-/- background, suggesting that a large amount of IFN-γ in SOCS1-deficient T cells suppressed Th17 differentiation. IL-6 plus TGF-β enhanced retinoic acid receptor-related orphan receptor (ROR)-γt expression and suppressed IFN-γ production in wild-type T cells, whereas these effects were severely impaired in SOCS1-deficient T cells. These phenotypes can be partly explained by STAT3 suppression by enhanced SOCS3 induction through hyper-STAT1 activation in SOCS1-deficient T cells. In addition, SOCS1-deficient T cells were much less sensitive to TGF-β. Suppression of Th1 differentiation by TGF-β was impaired in SOCS1-deficient T cells. TGF-β-mediated Smad transcriptional activity was severely inhibited in SOCS1-deficient cells in the presence of IFN-γ. Such impairment of TGF-γ functions were not observed in SOCS3-overexpressed cells, indicating that suppression of Smads was independent of SOCS3. Therefore, SOCS1 is necessary for Th17 differentiation by suppressing antagonistic effect of IFN-γ on both STAT3 and Smads. Induction of SOCS3 can partly explain IFN-γ-mediated STAT3 suppression, while other mechanism(s) will be involved in IFN-β-mediated Smad suppression. SOCS1-deficient T cells will be very useful to investigate the molecular mechanism for the STAT1-mediated suppression of Th17 development..
43. Yumiko Matsumura, Takashi Kobayashi, Kenji Ichiyama, Ryoko Yoshida, Masayuki Hashimoto, Tomohito Takimoto, Kentaro Tanaka, Takatoshi Chinen, Takashi Shichita, Tony Wyss-Coray, Katsuaki Sato, Akihiko Yoshimura, Selective expansion of Foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells, Journal of Immunology, 10.4049/jimmunol.179.4.2170, 179, 4, 2170-2179, 2007.08, Dendritic cells (DCs) induce immunity and immunological tolerance as APCs. It has been shown that DCs secreting IL-10 induce IL-10+ Tr1-type regulatory T (Treg) cells, whereas Foxp3-positive Treg cells are expanded from naive CD4+ T cells by coculturing with mature DCs. However, the regulatory mechanism of expansion of Foxp3+ Treg cells by DCs has not been clarified. In this study, we demonstrated that suppressors of cytokine signaling (SOCS)-3-deficient DCs have a strong potential as Foxp3+ T cell-inducing tolerogenic DCs. SOCS3-/- DCs expressed lower levels of class II MHC, CD40, CD86, and IL-12 than wild-type (WT)-DCs both in vitro and in vivo, and showed constitutive activation of STAT3. Foxp3- effector T cells were predominantly expanded by the priming with WT-DCs, whereas Foxp3+ Treg cells were selectively expanded by SOCS3-/- DCs. Adoptive transfer of SOCS3-/- DCs reduced the severity of experimental autoimmune encephalomyelitis. Foxp3+ T cell expansion was blocked by anti-TGF-β Ab, and SOCS3-/- DCs produced higher levels of TGF-β than WT-DCs, suggesting that TGF-β plays an essential role in the expansion of Foxp3+ Treg cells. These results indicate an important role of SOCS3 in determining on immunity or tolerance by DCs..
44. Akihiko Yoshimura, Kentaro Tanaka, Fuyuki Okamoto, Takashi Kobayashi, Intracellular negative signals and allergy, Arerugī = [Allergy], 56, 6, 563-569, 2007.01.
45. Maiko Moriyama, Satoru Fukuyama, Hiromasa Inoue, Takafumi Matsumoto, Takahiro Sato, Kentaro Tanaka, Ichiko Kinjyo, Tatsuhiko Kano, Akihiko Yoshimura, Masayasu Kojima, The neuropeptide neuromedin U activates eosinophils and is involved in allergen-induced eosinophilia, American Journal of Physiology - Lung Cellular and Molecular Physiology, 10.1152/ajplung.00345.2005, 290, 5, 2006.05, Neuromedin U (NMU) is a neuropeptide expressed not only in the central nervous system but also in various organs, including the gastrointestinal tract and lungs. NMU interacts with two G protein-coupled receptors, NMU-R1 and NMU-R2. Although NMU-R2 is expressed in a specific region of the brain, NMU-R1 is expressed in various peripheral tissues, including immune and hematopoietic cells. Our recent study demonstrated an important role of NMU in mast cell-mediated inflammation. In this study, we showed that airway eosinophilia was reduced in NMU-deficient mice in an allergen-induced asthma model. There were no differences in the antigen-induced Th2 responses between wild-type and NMU knockout mice. NMU-R1 was highly expressed in the eosinophil cell line, and NMU directly induced Ca2+ mobilization and extracellular/signal- regulated kinase phosphorylation. NMU also induced cell adhesion to components of the extracellular matrix (fibronectin and collagen type I), and chemotaxis in vitro. Furthermore, NMU-R1 was also expressed in human peripheral blood eosinophils, and NMU induced cell adhesion in a dose-dependent manner. These data indicate that NMU promotes eosinophil infiltration into inflammatory sites by directly activating eosinophils. Our study suggests that NMU receptor antagonists could be novel targets for pharmacological inhibition of allergic inflammatory diseases, including asthma..
46. Toshikatsu Hanada, Kentaro Tanaka, Yumiko Matsumura, Moriyasu Yamauchi, Hitomi Nishinakamura, Hiroyuki Aburatani, Ryuichi Mashima, Masato Kubo, Takashi Kobayashi, Akihiko Yoshimura, Induction of hyper Th1 cell-type immune responses by dendritic cells lacking the suppressor of cytokine signaling-1 gene, Journal of Immunology, 10.4049/jimmunol.174.7.4325, 174, 7, 4325-4332, 2005.04, Suppressor of cytokine signaling (SOCS1/JAB) has been shown to play an important role in regulating dendritic cell (DC) function and suppressing inlammatory diseases and systemic autoimmunity. However, role of SOCS1 in DCs for the initiation of Th cell response has not been clarified. Here we demonstrate that SOCS1-deficient DCs induce stronger Th1-type responses both in vitro and in vivo. SOCS1-deficient DCs induced higher IFN-γ production from naive T cells than wild-type (WT) DCs in vitro. Lymph node T cells also produced a higher amount of IFN-γ when SOCS1-deficient bone marrow-derived DCs (BMDCs) were transferred in vivo. Moreover, SOCS1-/- BMDCs raised more effective anti-tumor immunity than WT BMDCs. Microarray analysis revealed that IFN-inducible genes were highly expressed in SOCS1-deficient DCs without IFN stimulation, suggesting hyper STAT1 activation in SOCS1 -/- DCs. These phenotypes of SOCS1-deicient DCs were similar to those of CD8α+ DCs, and in the WT spleen, SOCS1 is expressed at higher levels in the Th2-inducing CD4+ DC subset, relative to the Th1-inducing CD8α+ DC subset. We propose that reduction of the SOCS1 gene expression in DCs leads to CD8α+ DC-like phenotype which promotes Th1-type hyperresponses..
47. Toshikatsu Hanada, Hiroki Yoshida, Seiya Kato, Kentaro Tanaka, Kosuke Masutani, Jun Tsukada, Yoshio Nomura, Hiromitsu Mimata, Masato Kubo, Akihiko Yoshimura, Suppressor of cytokine signaling-1 is essential for suppressing dendritic cell activation and systemic autoimmunity, Immunity, 10.1016/S1074-7613(03)00240-1, 19, 3, 437-450, 2003.09, Suppressor of cytokine signaling-1 (SOCS1/JAB) negatively regulates not only the cytokine-signaling pathway but also lipopolysaccharide (LPS)-induced macrophage activation. We found that SOCS1-deficient dendritic cells (DCs) were also hyperresponsive to interferon-γ and interleukin-4. To define the role of SOCS1-deficient DCs in vivo, we generated mice in which the SOCS1 expression was restored in T and B cells on a SOCS1-/- background. In these mice, DCs were accumulated in the thymus and spleen and produced high levels of BAFF/BLyS and APRIL, resulting in the aberrant expansion of B cells and autoreactive antibody production. SOCS1-deficient DCs efficiently stimulated B cell proliferation in vitro and autoantibody production in vivo. These results indicate that SOCS1 plays an essential role in the normal DC functions and suppression of systemic autoimmunity..