Enhancement of the antitumor effect of HER2-directed CAR-T cells through blocking epithelial-mesenchymal transition in tumor cells

  • FASEB J. 2020 Aug;34(8):11185-11199. doi: 10.1096/fj.202000080RR.
Peng-Fei Zhang  1 ,  Yong Huang  2 ,  Xiao Liang  1 ,  Dan Li  2 ,  Lin Jiang  2 ,  Xiao Yang  2 ,  Min Zhu  2 ,  Hong-Feng Gou  1 ,  You-Ling Gong  1 ,  Yu-Quan Wei  1  2 ,  Qiu Li  1  2 ,  Wei Wang  2
Affiliations
  • 1. Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
  • 2. State Key Laboratory of Biotherapy, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
PMID: 32645243 DOI: 10.1096/fj.202000080RR
Abstract

The efficacy of chimeric antigen receptor T (CAR-T) cell therapy in solid tumors is far from satisfactory. In this study, we investigated the influence of epithelial-mesenchymal transition (EMT) on the antitumor effect of CAR-T cells and explored the potential efficacy of combining CAR-T cells with inhibitors targeting EMT. We successfully induced EMT in tumor cells with TGF-β1, and the antitumor effect of HER2-directed CAR-T cells was significantly suppressed by EMT. Upregulation of PD-L1 was observed in tumor cells undergoing EMT, and change in PD-L1 expression during the EMT process was dependent on the MEK/ERK and PI3K/Akt pathways. Inhibition of the TGF-β1 pathway could block the EMT process in tumor cells and restore their susceptibility to HER2-directed CAR-T cells in vitro. In addition, targeting the TGF-β1 pathway significantly enhanced the antitumor effect of HER2-directed CAR-T cells in vivo. Our findings suggest that blocking EMT could potently enhance the antitumor effect of CAR-T cells, which provides a promising approach to improving the therapeutic efficacy of CAR-T cell therapy in solid tumors.

Keywords
adoptive cell transfer; chimeric antigen receptor; epithelial-mesenchymal transition; solid tumor.
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