Function And Molecular Mechanisms Of Epidermal Growth Factor Receptor-targeted Chimeric Antigen Receptor T Cells In Triple Negative Breast Cancer And The Combined Therapeutic Strategies

Epidermal growth factor receptor-targeted chimeric antigen receptor T cell(EGFR CAR-T)is potent and specific in suppressing triple-negative breast cancer(TNBC)cell growth in vitro and in vivo.However,a subset of mice soon acquired resistance,which limits the potential use of EGFR CAR-T.The aim of this study is to find a way to overcome the observed resistance.Transcriptomic analysis results revealed that EGFR CAR-T treatment led to the induction of a cohort of immunosuppressive genes,presumably through interferon gamma(IFNγ)signaling,in EGFR CAR-T-resistant TNBC tumors.EGFR CAR-T-induced immunosuppressive genes were found to be associated with EGFR CAR-T-activated enhancers and especially sensitive to THZ1,a CDK7 inhibitor,out of a panel of small molecules targeting epigenetic modulators screened.Accordingly,combination therapy of THZ1 and EGFR CAR-T suppressed immune resistance and tumor growth and metastasis in TNBC tumor models including human MDA-MB-231 cells-derived xenografts,TNBC patient-derived xenografts,and EGFR CAR-T-resistant TNBC xenografts.Taken together,we demonstrated that CART therapy-induced immune resistance can be overcome by transcriptional modulation using epigenetic inhibitors,providing a therapeutic avenue for treating TNBC in the clinic.