figshare
Browse

sorry, we can't preview this file

21598290cd200812-sup-244871_3_supp_6826067_qmj3gr.docx (32.32 MB)

Supplementary Figures from Therapeutically Increasing MHC-I Expression Potentiates Immune Checkpoint Blockade

Download (32.32 MB)
journal contribution
posted on 2023-04-03, 23:40 authored by Shengqing Stan Gu, Wubing Zhang, Xiaoqing Wang, Peng Jiang, Nicole Traugh, Ziyi Li, Clifford Meyer, Blair Stewig, Yingtian Xie, Xia Bu, Michael P. Manos, Alba Font-Tello, Evisa Gjini, Ana Lako, Klothilda Lim, Jake Conway, Alok K. Tewari, Zexian Zeng, Avinash Das Sahu, Collin Tokheim, Jason L. Weirather, Jingxin Fu, Yi Zhang, Benjamin Kroger, Jin Hua Liang, Paloma Cejas, Gordon J. Freeman, Scott Rodig, Henry W. Long, Benjamin E. Gewurz, F. Stephen Hodi, Myles Brown, X. Shirley Liu

Supplementary Figures S1-S8

Funding

NIH

History

ARTICLE 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. 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

Usage metrics

    Cancer Discovery

    Categories

    Keywords

    Computational MethodsGene RegulationGenome BiologyFunctional genomicsImmunotherapyCheckpoint blockade

    Licence

    CC BY

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC