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Therapeutically Increasing MHC-I Expression Potentiates Immune Checkpoint Blockade
Shengqing Stan Gu1,2, Wubing Zhang1,3, Xiaoqing Wang4
1Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
Abstract:
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.
Insights
This study identifies SMAC mimetics, like birinapant, as drugs that can increase MHC-I expression. This approach may help overcome resistance to immune checkpoint blockade (ICB) therapy in cancer patients with low MHC-I levels.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Immune checkpoint blockade (ICB) therapy is effective for cancer, but resistance occurs, often due to impaired MHC-I expression.
- Identifying therapeutic strategies to restore MHC-I expression is crucial for improving ICB efficacy.
Purpose of the Study:
- To identify drugs that upregulate MHC-I expression without increasing PD-L1.
- To explore novel therapeutic approaches for enhancing ICB response in tumors with low MHC-I.
Main Methods:
- Utilized FACS-based genome-wide CRISPR screens to identify regulators of MHC-I.
- Employed a data-mining approach to screen for drugs with specific transcriptional signatures.
- Experimentally validated the efficacy of identified drug candidates in preclinical models.
Main Results:
- TRAF3 was identified as a negative regulator of MHC-I expression.
- A gene expression signature associated with TRAF3 loss correlated with improved survival and ICB response.
- Second Mitochondria-derived Activator of Caspase (SMAC) mimetics, specifically birinapant, were found to upregulate MHC-I and enhance T cell-mediated killing.
- Birinapant demonstrated additive efficacy with ICB in preclinical settings.
Conclusions:
- SMAC mimetics, such as birinapant, represent a promising strategy to enhance ICB efficacy in tumors with low MHC-I expression.
- This approach offers potential new immunotherapy opportunities for refractory cancer patients.
- The methodology can be generalized to discover other drugs that potentiate immunotherapy.
