Therapeutically Increasing MHC-I Expression Potentiates Immune Checkpoint Blockade.

Autor:	Gu SS; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts., Zhang W; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.; School of Life Science and Technology, Tongji University, Shanghai, China., Wang X; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Jiang P; Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Traugh N; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Li Z; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.; School of Life Science and Technology, Tongji University, Shanghai, China., Meyer C; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts., Stewig B; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Xie Y; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts., Bu X; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Manos MP; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Font-Tello A; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts., Gjini E; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Lako A; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Lim K; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts., Conway J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Tewari AK; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Zeng Z; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts., Sahu AD; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts., Tokheim C; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts., Weirather JL; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Fu J; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.; School of Life Science and Technology, Tongji University, Shanghai, China., Zhang Y; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts., Kroger B; The University of Texas Southwestern Medical School, Dallas, Texas., Liang JH; Department of Microbiology, Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., Cejas P; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts., Freeman GJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Rodig S; Department of Pathologic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Long HW; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts., Gewurz BE; Department of Microbiology, Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., Hodi FS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Brown M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. xsliu@ds.dfci.harvard.edu myles_brown@dfci.harvard.edu.; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts., Liu XS; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts. xsliu@ds.dfci.harvard.edu myles_brown@dfci.harvard.edu.; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2021 Jun; Vol. 11 (6), pp. 1524-1541. Date of Electronic Publication: 2021 Feb 15.
DOI:	10.1158/2159-8290.CD-20-0812
Abstrakt:	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 NFκB 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-naïve 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. This article is highlighted in the In This Issue feature, p. 1307 . (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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