Immune-mediated mechanisms of resistance to molecular targeting therapy against NSCLC

• Project/Area Number: 26290050
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Keio University
• Principal Investigator: Jinushi Masahisa 慶應義塾大学, 医学部, 特任准教授 (40318085)
• Co-Investigator(Kenkyū-buntansha): 菰原 義弘 熊本大学, その他の研究科, 准教授 (40449921)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000); Fiscal Year 2016: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2015: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2014: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
• Keywords: 腫瘍免疫 / 肺腺癌 / ミエロイド細胞 / PD-1 / EGFR-TKI / 治療抵抗性 / 非小細胞癌 / EGFR変異 / マクロファージ / 癌 / 免疫 / 免疫チェックポイント分子 / 非小細胞肺癌 / 肺非小細胞癌

Outline of Final Research Achievements

As immune-mediated factors which are critical to reduce sensitibity and/or trigger resistance to EGF-TKI agains NSCLC through the analysis of novel spontaneous NSCLC models and clinical samples, we identified signaling pathways related to differentiation and activation of M2 macrophages and MDSC, two major immunosuppressive myeloid cells, as important factor to predict low sensitivity and emergence of resistant-associated mutation (T790M) to EGF-TKI against lung adenocarcinoma. Moreover, the combination of CSF1 inhibitors and EGF^TKI dramatically reduced incidence of spontaneous lung adenocarcinoma in mouse models. On the other hands, there are no involvement of immune checkpoint pathways as immune factors to regulate lung adenocarcinoma.It is important to clarify novel immune-mediated mechanisms other than immune checkpoint such as PD-1 to regulate responsiveness of EGFR-TKI against lung adenocarcinomas.

Research Products

• [Journal Article] Interleukin-17A Promotes Lung Tumor Progression Through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade (2017)
  • Author(s): Akbay EA, Koyama S, Liu Y, Dries R, Bufe LE2, Silkes M, Jones R, Jinushi M, Kulkarni M, Carretero J, etal.
  • Journal Title: Journal of Thoracic Oncology Volume: 印刷中
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel chemoimmunotherapeutic strategy for hepatocellular carcinoma based on a genome-wide association study. (2017)
  • Author(s): Goto K, Annan DA, Morita T, Li W, Muroyama R, Matsubara Y, Ito S, Nakagawa R, Tanoue Y, Jinushi M, Kato N.
  • Journal Title: Ｓｃｉｅｎｔｉｆｉｃ Ｒｅｐｏｒｔｓ Volume: ６
  • DOI: 10.1038/srep38407
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TIM-3 expression in lymphoma cells predicts chemoresistance in patients with adult T-cell leukemia/lymphoma. (2017)
  • Author(s): Horlad H, Ohnishi K, Ma C, Fujiwara Y, Niino D, Ohshima K, Jinushi M, Matsuoka M, Takeya M, Komohara Y.
  • Journal Title: Oncology Letters Volume: 12 Pages: 1519-1524
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of the autonomic nervous system in the tumor micro-environment and its therapeutic potential. (2017)
  • Author(s): Xu Z, Shioda S, Jinushi M, Kawakami Y, Ohtaki H, Wang S, Zhao X, Liu Y, Zhou D, Guo Y.
  • Journal Title: Current Pharmaceitical Design Volume: 印刷中
  • Int'l Joint Research
• [Journal Article] Induction of protumoral CD11c(high) macrophages by glioma cancer stem cells through GM-CSF. (2016)
  • Author(s): Kokubu et al
  • Journal Title: Gene to Cell Volume: 21 Pages: 241-251
  • DOI: 10.1111/gtc.12333
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] MFG-E8 Is Critical for Embryonic Stem Cell-Mediated T Cell Immunomodulation. (2015)
  • Author(s): Tan Y, AlKhamees B, Jia D, Li L, Couture JF, Figeys D, Jinushi M, Wang L.
  • Journal Title: Stem Cell Reports Volume: 5(5) Pages: 741-52
  • DOI: 10.1016/j.stemcr.2015.09.005
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The Coordinated Actions of TIM-3 on Cancer and Myeloid Cells in the Regulation of Tumorigenicity and Clinical Prognosis in Clear Cell Renal Cell Carcinomas. (2015)
  • Author(s): Yoshihiro Komohara, Tomoko Morita, Dorcas A. Annan, Hasita Horlad, Koji Ohnishi, Sohsuke Yamada, Toshiyuki Nakayama, Shohei Kitada, Shinya Suzu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Koichi Akashi, Motohiro Takeya, Masahisa Jinushi
  • Journal Title: Cancer Immunology Research Volume: 3 Pages: 999-1007
  • DOI: 10.1158/2326-6066.cir-14-0156
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tumor-associated macrophages as an emerging target against tumors: Creating a new path from bench to bedside. [Review on Cancer] (2015)
  • Author(s): Jinushi M, Komohara Y
  • Journal Title: Biochim Biophys Acta Volume: 1855 Pages: 123-130
  • DOI: 10.1016/j.bbcan.2015.01.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Low expression levels of microRNA-124-5p correlated with poor prognosis in colorectal cancer via targeting of SMC4 (2014)
  • Author(s): Jinushi T, Shibayama Y, Kinoshita I, Oizumi S, Jinushi M, Aota T, Takahashi T, Horita S, Dosaka-Akita H, Iseki K.
  • Journal Title: Cancer Med. Volume: 3 Pages: 1544-1552
  • DOI: 10.1002/cam4.309
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Immune regulation of therapy-resistant niches: emerging targets for improving anticancer drug responses. (2014)
  • Author(s): Yamashina T, Baghdadi M, Yoneda A, Kinoshita I, Suzu S, Dosaka-Akita H, Jinushi M.
  • Journal Title: Cancer Metastasis Rev. Volume: 74 Pages: 2698-2709
  • DOI: 10.1158/0008-5472.can-13-2169
  • Peer Reviewed / Acknowledgement Compliant