Therapeutically Increasing MHC-I Expression Potentiates Immune Checkpoint Blockade

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

Mechanisms of MHC-I Downregulation and Role in Immunotherapy Response

“…BO-112 restored MHC-I expression through an NF-κB mediated mechanism and independent of NLRC5. A recent study used a CRISPR screening approach to identify factors that decouple the regulation of MHC-I and PD-L1 ( 99 ). It was found that depletion of TRAF3 upregulated MHC-I through the NF-κB pathway and TRAF3 small molecule inhibitors increased immuno-sensitivity of cancer cells specifically through MHC-I expression.…”

Intron retention-induced neoantigen load correlates with unfavorable prognosis in multiple myeloma

“…Collectively, these two mechanisms may partially explain why higher IR-induced neoantigen load in MM samples was not associated with better prognostic outcome. This result also suggests that splicing inhibitors could possibly boost the efficacy of immune checkpoint blockade therapy in MM by activating MHC-I presentation [ 46 , 47 ]. Further analysis with integrated multi-omics data from different aspects of the immune landscape is needed to further understand the potential determinants of responsiveness to cancer immunotherapies in MM.…”

Tumor immunology CRISPR screening: present, past, and future

“…Critical effectors have been identified through forward genetic approaches [92][93][94]. The discovery of these evasion mechanisms has greatly accelerated with CRISPR screening, which identified pathways involved in the upregulation of checkpoint inhibition [36,95,96], downregulation of MHC processing [70,95,97] altering cytokine signaling [98][99][100][101], and autophagy [102]. In their landmark paper, Manguso and colleagues performed a series of in vivo CRISPR screens in Tcra -/and C57BL6 mice treated with either irradiated tumor vaccine…”