期刊
CANCER IMMUNOLOGY RESEARCH
卷 9, 期 6, 页码 707-722出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-20-0405
关键词
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资金
- Natural Science Foundation of Fujian Province of China [2020J05018, 2020J02004]
- Fundamental Research Funds for the Central Universities [20720200104]
- Ministry of Science and Technology of China [2020YFA0112300, 2020YFA0803600]
- National Natural Science Foundation of China [81761128015, 81861130370, 31871319, 91953114]
- Fujian Province Health Education Joint Research Project [WKJ2016-2-09]
- Xiamen Science and Technology Project [2017S0091]
- Xiamen Science and Technology major projects [3502Z20171001-20170302]
- Fundamental Research Funds for the Central University [20720200002, 20720190145]
The study revealed that immunosuppressive genes induced by EGFR CAR T cells were sensitive to a CDK7 inhibitor THZ1, which can overcome resistance in TNBC tumors. Combination therapy with THZ1 and EGFR CAR T cells suppressed immune resistance, tumor growth, and metastasis in TNBC tumor models. This suggests that transcriptional modulation using epigenetic inhibitors could offer a potential avenue for treating TNBC in the clinic.
EGFR-targeted chimeric antigen receptor (CAR) T cells are potent and specific in suppressing the growth of triple-negative breast cancer (TNBC) in vitro and in vivo. However, in this study, a subset of mice soon acquired resistance, which limits the potential use of EGFR CAR T cells. We aimed to find a way to overcome the observed resistance. Transcriptomic analysis results revealed that EGFR CAR T-cell treatment induced a set of immunosuppressive genes, presumably through IFN gamma signaling, in EGFR CAR T-cell-resistant TNBC tumors. The EGFR CAR T-cell-induced immunosuppressive genes were associated with EGFR CAR T-cell-activated enhancers and were especially sensitive to THZ1, a CDK7 inhibitor we screened out of a panel of small molecules targeting epigenetic modulators. Accordingly, combination therapy with THZ1 and EGFR CAR T cells suppressed immune resistance, tumor growth, and metastasis in TNBC tumor models, including human MDA-MB-231 cell-derived and TNBC patient-derived xenografts, and mouse EMT6 cell-derived allografts. Taken together, we demonstrated that transcriptional modulation using epigenetic inhibitors could overcome CAR T-cell therapy-induced immune resistance, thus providing a therapeutic avenue for treating TNBC in the clinic.
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