期刊
CANCER DISCOVERY
卷 11, 期 6, 页码 1524-1541出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-20-0812
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资金
- NIH [R01CA234018, R01AI137337, P50CA101942-12, P50CA206963]
- Breast Cancer Research Foundation [BCRF-19-100]
- Burroughs Wellcome Career Award in Medical Sciences
- Sara Elizabeth O'Brien Trust Fellowship
This study identified that the SMAC mimetic birinapant can upregulate MHC-I expression and enhance cancer cell sensitivity to immunotherapy. The findings provide preclinical rationale for using SMAC mimetics to improve immunotherapy efficacy in tumors with low MHC-I expression.
Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a suppressor of the NF kappa B pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout gene expression signature is associated with better survival in ICB-naive patients with cancer and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified Second Mitochondria-derived Activator of Caspase (SMAC) mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T cell-dependent killing, and adds to ICB efficacy. Our findings provide preclinical rationale for treating tumors expressing low MHC-I expression with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy. SIGNIFICANCE: MHC-I loss or downregulation in cancer cells is a major mechanism of resistance to T cell-based immunotherapies. Our study reveals that birinapant may be used for patients with low baseline MHC-I to enhance ICB response. This represents promising immunotherapy opportunities given the biosafety profile of birinapant from multiple clinical trials.
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