Therapeutic decoupling of MHC-I and PD-L1 expression increases the efficacy of immune checkpoint blockade (koTRAF3_RNAseq)

ABSTRACT: Immune checkpoint blockade (ICB) therapy has revolutionized the treatment of multiple cancers, but the majority of patients remain refractory due to impaired MHC-I expression. Although the combination of immunotherapy with existing anti-cancer treatments has shown synergy in multiple scenarios, the immunomodulatory effects of conventional therapies remain poorly understood. Here, we integrated CRISPR-mediated genetic screens and data mining of perturbation associated gene expression data to identify drugs that can specifically up-regulate MHC-I without inducing PD-L1. Using FACS-based genome-wide CRISPR screens, we identified Traf3, a critical suppressor of the NF-κB pathway, as a suppressor of MHC-I, but not PD-L1. A Traf3-knockout gene expression signature is associated with better survival in ICB-naive cancer patients and better response to ICB in published clinical trials. From publicly available drug treatment data, we identified SMAC mimetics as the top candidates of having similar transcriptional effects as Traf3-knockout. We experimentally validated that the SMAC mimetic birinapant specifically up-regulated MHC-I, sensitized cancer cells to T-cell-dependent killing, and synergized with ICB in the treatment of established tumors. Our findings provide a strong preclinical rationale for treating MHC-I-low tumors with SMAC mimetics to enhance sensitivity to existing immunotherapy. Moreover, the integrated approach used in this study can be generalized to identify drugs with immunomodulatory effects to enhance immunotherapy efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE149824 | GEO | 2020/07/01

REPOSITORIES: GEO