Therapeutically Increasing MHC-I Expression Potentiates Immune Checkpoint Blockade
| Autor: | Henry W. Long, Blair Stewig, Alba Font-Tello, Xiaoqing Wang, Michael Manos, Ziyi Li, X. Shirley Liu, Jingxin Fu, Paloma Cejas, Gordon J. Freeman, Alok K. Tewari, Scott J. Rodig, Yi Zhang, Zexian Zeng, F. Stephen Hodi, Clifford A. Meyer, Yingtian Xie, Xia Bu, Wubing Zhang, Collin Tokheim, Avinash Das Sahu, Jason L. Weirather, Jake Conway, Klothilda Lim, Myles Brown, Jin Hua Liang, Evisa Gjini, Shengqing Stan Gu, Ana Lako, Peng Jiang, Benjamin Kroger, Nicole Traugh, Benjamin E. Gewurz |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
T cell medicine.medical_treatment B7-H1 Antigen Article 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Neoplasms MHC class I Tumor Microenvironment Data Mining Humans Medicine Immune Checkpoint Inhibitors biology business.industry Gene Expression Profiling Histocompatibility Antigens Class I Cancer Immunotherapy medicine.disease Immune checkpoint Blockade 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer cell Cancer research biology.protein business |
| Zdroj: | Cancer Discov |
| ISSN: | 2159-8290 2159-8274 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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