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論文 - 榎本　篤

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Significance of meflin-positive cancer-associated fibroblasts in predicting response to immune checkpoint inhibitors in non-small cell lung cancer.

Miyai, Y; Enomoto, A; Ando, Y; Takahashi, M

JOURNAL OF CLINICAL ONCOLOGY 38 巻 ( 15 ) 2020年5月

Significance of meflin-positive cancer-associated fibroblasts in predicting response to immune checkpoint inhibitors in non-small cell lung cancer.

Yuki Miyai, Atsushi Enomoto, Yuichi Ando, Masahide Takahashi

Journal of Clinical Oncology 38 巻 ( 15_suppl ) 頁： 3118 - 3118 2020年5月

掲載種別：研究論文（学術雑誌）出版者・発行元：American Society of Clinical Oncology (ASCO)

3118

Background: Tumor immunity is regulated by complex interactions between cancer and immune cells, which also involves other components of the tumor microenvironment (TME). Recently, cancer-associated fibroblasts (CAFs), a major constituent of the TME, have emerged as important regulators of tumor immunity. Specifically, for example, α-smooth muscle actin or leucine-rich repeat containing 15-positive CAFs have been shown to be crucial for the suppression of tumor immunity. However, a comprehensive picture of how other CAF subset(s) are involved in tumor immunity is still lacking. Here, we show the involvement of a CAF subset highly expressing Meflin, which was recently identified as a marker of cancer-restraining CAFs in pancreatic cancer (Mizutani et al., Cancer Res, 2019), in the response of non-small cell lung cancer (NSCLC) patients to immune checkpoint inhibitors (ICIs). Methods: A sample cohort of 122 subjects with NSCLC who had received ICI monotherapy with nivolumab, pembrolizumab, or atezolizumab was identified at the Department of Respiratory Medicine at Nagoya University Hospital. We selected 92 eligible patients, collected formalin-fixed paraffin-embedded tumor tissues, and prepared 4–µm-thick slides for the analysis of Meflin expression by RNA-in situ hybridization assay, followed by the evaluation of treatment response of 88 patients using the iRECIST criteria. We assessed the number of Meflin-positive CAFs and divided the patients into Meflin-High (20% and more CAFs express Meflin) and -Low groups. The cut-off value was obtained by the ROC analysis. Primarily, objective response rate (ORR) was compared between Meflin-High and –Low groups. Overall survival (OS), and progression free survival (PFS) were also assessed. Results: Patients who started to receive ICIs till the end of March 2019 were enrolled and followed-up until the end of 2019. Analysis of the tumor tissues revealed that 24 (40.7%) of 59 Meflin-High patients responded to the ICI monotherapy. In contrast, none (0%) of 29 Meflin-Low patients showed any significant response (p-value: 0.0000174). Meflin-High groups showed statistically significant prolongations in both OS and PFS with the hazard ratios of 0.3114 [0.1591-0.6094] and 0.3997 [0.2290-0.6976], respectively. Conclusions: This retrospective observation indicated that the high infiltration of Meflin-positive CAFs may shape tumor-suppressive immune response and increase the sensitivity to ICIs, which differs from those of other CAF subsets.

DOI： 10.1200/jco.2020.38.15_suppl.3118

Cancer-associated fibroblasts that restrain cancer progression: Hypotheses and perspectives 査読有り国際誌

Miyai, Y; Esaki, N; Takahashi, M; Enomoto, A

CANCER SCIENCE 111 巻 ( 4 ) 頁： 1047 - 1057 2020年4月

The Role of Meflin Expression in Fibroblasts During Development of Pulmonary Fibrosis

Hashimoto, N; Nakahara, Y; Sakamoto, K; Enomoto, A; Yokoi, T; Suzuki, A; Inoue, M; Wakahara, K; Hasegawa, Y

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 201 巻 2020年

Meflin-positive cancer-associated fibroblasts inhibit pancreatic carcinogenesis

Mizutani, Y; Kobayashi, H; Enomoto, A; Takahashi, M

CANCER RESEARCH 79 巻 ( 24 ) 2019年12月

Protein Kinase N Promotes Stress-Induced Cardiac Dysfunction Through Phosphorylation of Myocardin-Related Transcription Factor A and Disruption of Its Interaction With Actin 査読有り国際誌

Sakaguchi, T; Takefuji, M; Wettschureck, N; Hamaguchi, T; Amano, M; Kato, K; Tsuda, T; Eguchi, S; Ishihama, S; Mori, Y; Yura, Y; Yoshida, T; Unno, K; Okumura, T; Ishii, H; Shimizu, Y; Bando, YK; Ohashi, K; Ouchi, N; Enomoto, A; Offermanns, S; Kaibuchi, K; Murohara, T

CIRCULATION 140 巻 ( 21 ) 頁： 1737 - 1752 2019年11月

Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis 査読有り国際誌

Mizutani, Y; Kobayashi, H; Iida, T; Asai, N; Masamune, A; Hara, A; Esaki, N; Ushida, K; Mii, S; Shiraki, Y; Ando, K; Weng, L; Ishihara, S; Ponik, SM; Conklin, MW; Haga, H; Nagasaka, A; Miyata, T; Matsuyama, M; Kobayashi, T; Fujii, T; Yamada, S; Yamaguchi, J; Wang, TT; Woods, SL; Worthley, D; Shimamura, T; Fujishiro, M; Hirooka, Y; Enomoto, A; Takahashi, M

CANCER RESEARCH 79 巻 ( 20 ) 頁： 5367 - 5381 2019年10月

The new-defined mesenchymal stromal/stem cell marker has a protective role in the development of acute lung injury

Nakahara, Y; Hashimoto, N; Sakamoto, K; Ando, A; Inoue, M; Suzuki, A; Enomoto, A; Hasegawa, Y

EUROPEAN RESPIRATORY JOURNAL 54 巻 2019年9月

TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets 査読有り国際誌

Araki, K; Araki, A; Honda, D; Izumoto, T; Hashizume, A; Hijikata, V; Yamada, S; Iguchi, Y; Hara, A; Ikumi, K; Kawai, K; Ishigaki, S; Nakamichi, Y; Tsunekawa, S; Seino, Y; Yamamoto, A; Takayama, Y; Hidaka, S; Tominaga, M; Ohara-Imaizumi, M; Suzuki, A; Ishiguro, H; Enomoto, A; Yoshida, M; Arima, H; Muramatsu, SI; Sobue, G; Katsuno, M

JOURNAL OF CLINICAL INVESTIGATION 129 巻 ( 9 ) 頁： 3578 - 3593 2019年9月

Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin in Cardiac Tissue Repair and the Development of Diastolic Dysfunction 査読有り国際誌

Hara, A; Kobayashi, H; Asai, N; Saito, S; Higuchi, T; Kato, K; Okumura, T; Bando, YK; Takefuji, M; Mizutani, Y; Miyai, Y; Saito, S; Maruyama, S; Maeda, K; Ouchi, N; Nagasaka, A; Miyata, T; Mii, S; Kioka, N; Worthley, DL; Murohara, T; Takahashi, M; Enomoto, A

CIRCULATION RESEARCH 125 巻 ( 4 ) 頁： 414 - 430 2019年8月

The intercellular expression of type-XVII collagen, laminin-332, and integrin-β1 promote contact following during the collective invasion of a cancer cell population 査読有り国際誌

Kumagai, Y; Nio-Kobayashi, J; Ishida-Ishihara, S; Tachibana, H; Omori, R; Enomoto, A; Ishihara, S; Haga, H

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 514 巻 ( 4 ) 頁： 1115 - 1121 2019年7月

Identification of cancer-associated fibroblasts that suppress pancreatic cancer progression

Enomoto, A; Mizutani, Y; Kobayashi, H; Iida, T; Woods, SL; Worthley, DL; Takahashi, M

CANCER RESEARCH 79 巻 ( 13 ) 2019年7月

Dephosphorylation of Girdin by PP2A inhibits breast cancer metastasis 査読有り

Li, J; Enomoto, A; Weng, L; Sun, LQ; Takahashi, M

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 513 巻 ( 1 ) 頁： 28 - 34 2019年5月

Cancer-associated fibroblasts in gastrointestinal cancer 査読有り

Kobayashi, H; Enomoto, A; Woods, SL; Burt, AD; Takahashi, M; Worthley, DL

NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY 16 巻 ( 5 ) 頁： 282 - 295 2019年5月

CD109: a multifunctional GPI-anchored protein with key roles in tumor progression and physiological homeostasis 査読有り国際誌

Mii, S; Enomoto, A; Shiraki, Y; Taki, T; Murakumo, Y; Takahashi, M

PATHOLOGY INTERNATIONAL 69 巻 ( 5 ) 頁： 249 - 259 2019年5月

Aberrant Active <i>cis</i>-Regulatory Elements Associated with Downregulation of RET Finger Protein Overcome Chemoresistance in Glioblastoma 査読有り国際誌

Ranjit, M; Hirano, M; Aoki, K; Okuno, Y; Ohka, F; Yamamichi, A; Kato, A; Maeda, S; Motomura, K; Matsuo, K; Enomoto, A; Ino, Y; Todo, T; Takahashi, M; Wakabayashi, T; Kato, T; Natsume, A

CELL REPORTS 26 巻 ( 9 ) 頁： 2274 - + 2019年2月

Cancer-associated fibroblasts in gastrointestinal cancer 査読有り

Kobayashi H, Enomoto A, Woods SL, Burt AD, Takahashi M, Worthley DL.

Nat Rev Gastroenterol Hepatol. 2019年2月

Aberrant Active cis-Regulatory Elements Associated with Downregulation of RET Finger Protein Overcome Chemoresistance in Glioblastoma 査読有り

Ranjit M, Hirano M, Aoki K, Okuno Y, Ohka F, Yamamichi A, Kato A, Maeda S, Motomura K, Matsuo K, Enomoto A, Ino Y, Todo T, Takahashi M, Wakabayashi T, Kato T, Natsume A.

Cell Rep 26 巻 ( 9 ) 頁： 2274-2281.e5. 2019年2月

A rare pseudo tumour in the extraembryonic coelom in first trimester of pregnancy: ultrasound and pathology 査読有り国際誌

Sumigama, S; Enomoto, A; Matsukawa, S; Ushida, T; Imai, K; Nakano, T; Kotani, T; Kikkawa, F

JOURNAL OF OBSTETRICS AND GYNAECOLOGY 39 巻 ( 4 ) 頁： 545 - 546 2019年

Force-dependent arrest of keratinocyte proliferation and its potential defect in skin cancer.

Hirata, H; Enomoto, A; Sunagawa, M; Dobrokhotov, O; Takahashi, M; Samsonov, M; Sokabe, M

MOLECULAR BIOLOGY OF THE CELL 29 巻 ( 26 ) 2018年12月

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