Galunisertib enhances chimeric antigen receptor-modified T cell function

  • Zhixiong Wang School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China.
  • Qian Liu School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China. https://orcid.org/0000-0001-7405-7788
  • Na Risu Division of Health Science, Graduate School of Medicine, Osaka University, Osaka, Japan.
  • Jiayu Fu Division of Health Science, Graduate School of Medicine, Osaka University, Osaka, Japan.
  • Yan Zou Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai, China.
  • Jiaxing Tang Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai, China.
  • Long Li Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai, China. https://orcid.org/0000-0001-7536-443X
  • Hui Liu Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai, China. https://orcid.org/0000-0002-4568-8051
  • Guomin Zhou School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China. https://orcid.org/0000-0001-7507-2373
  • Xuekai Zhu | zhuxk@shanghaitech.edu.cn https://orcid.org/0000-0002-4297-8854

Abstract

Chimeric antigen receptor (CAR) T cell therapy still faces the challenge of immunosuppression when treating solid tumors. TGF-β is one of the critical factors in the tumor microenvironment to help tumors escape surveillance by the immune system. Here we tried using the combination of a small molecule inhibitor of TGF-β receptor I, Galunisertib, and CAR T cells to explore whether Galunisertib could enhance CAR T cell function against solid tumor cells. In vitro experiments showed Galunisertib could significantly enhance the specific cytotoxicity of both CD133- and HER2-specific CAR T cells. However, Galunisertib had no direct killing effect on target cells. Galunisertib significantly increased the cytokine secretion of CAR T cells and T cells that do not express CAR (Nontransfected T cells). Galunisertib did not affect the proliferation of T cells, the antigen expression on target cells and CD69 on CAR T cells. We found that TGF-β was secreted by T cells themselves upon activation, and Galunisertib could reduce TGF-β signaling in CAR T cells. Our findings can provide the basis for further preclinical and clinical studies of the combination of Galunisertib and CAR T cells in the treatment of solid tumors.

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Author Biography

Zhixiong Wang, School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai

Ma’anshan University, Ma’anshan, China
Division of Health Science, Graduate School of Medicine, Osaka University, Osaka, Japan

Published
2020-06-19
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Issue
Section
Special Issue - Stem cells and regenerative medicine
Keywords:
CAR T, TGF-β, solid tumor, immunotherapy, immunosuppression
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How to Cite
Wang, Z., Liu, Q., Risu, N., Fu, J., Zou, Y., Tang, J., Li, L., Liu, H., Zhou, G., & Zhu, X. (2020). Galunisertib enhances chimeric antigen receptor-modified T cell function. European Journal of Histochemistry, 64(s2). https://doi.org/10.4081/ejh.2020.3122