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 NF-kB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout (Traf3-KO) gene expression signature is associated with better survival in ICB-naive cancer patients and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified 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.
%0 Journal Article
%1 Gucandisc.0812.2020
%A Gu, Shengqing Stan
%A Zhang, Wubing
%A Wang, Xiaoqing
%A Jiang, Peng
%A Traugh, Nicole
%A Li, Ziyi
%A Meyer, Clifford
%A Stewig, Blair
%A Xie, Yingtian
%A Bu, Xia
%A Manos, Michael P
%A Font-Tello, Alba
%A Gjini, Evisa
%A Lako, Ana
%A Lim, Klothilda
%A Conway, Jake
%A Tewari, Alok K
%A Zeng, Zexian
%A Das Sahu, Avinash
%A Tokheim, Collin
%A Weirather, Jason L
%A Fu, Jingxin
%A Zhang, Yi
%A Kroger, Benjamin
%A Liang, Jin Hua
%A Cejas, Paloma
%A Freeman, Gordon J.
%A Rodig, Scott
%A Long, Henry W.
%A Gewurz, Benjamin E
%A Hodi, F. Stephen
%A Brown, Myles
%A Liu, X. Shirley
%D 2021
%I American Association for Cancer Research
%J Cancer Discovery
%K Class I MHC PD-l1 TRAF3 antigen checkpoint immuno-oncology myown presentation
%R 10.1158/2159-8290.CD-20-0812
%T Therapeutically increasing MHC-I expression potentiates immune checkpoint blockade
%U https://cancerdiscovery.aacrjournals.org/content/early/2021/02/15/2159-8290.CD-20-0812
%X 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 NF-kB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout (Traf3-KO) gene expression signature is associated with better survival in ICB-naive cancer patients and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified 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.
@article{Gucandisc.0812.2020,
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 NF-kB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout (Traf3-KO) gene expression signature is associated with better survival in ICB-naive cancer patients and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified 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.},
added-at = {2021-02-18T19:03:02.000+0100},
author = {Gu, Shengqing Stan and Zhang, Wubing and Wang, Xiaoqing and Jiang, Peng and Traugh, Nicole and Li, Ziyi and Meyer, Clifford and Stewig, Blair and Xie, Yingtian and Bu, Xia and Manos, Michael P and Font-Tello, Alba and Gjini, Evisa and Lako, Ana and Lim, Klothilda and Conway, Jake and Tewari, Alok K and Zeng, Zexian and Das Sahu, Avinash and Tokheim, Collin and Weirather, Jason L and Fu, Jingxin and Zhang, Yi and Kroger, Benjamin and Liang, Jin Hua and Cejas, Paloma and Freeman, Gordon J. and Rodig, Scott and Long, Henry W. and Gewurz, Benjamin E and Hodi, F. Stephen and Brown, Myles and Liu, X. Shirley},
biburl = {https://www.bibsonomy.org/bibtex/26e1a6a8885424e4d3da5d72a3bad96a3/bgewurz},
doi = {10.1158/2159-8290.CD-20-0812},
elocation-id = {candisc.0812.2020},
eprint = {https://cancerdiscovery.aacrjournals.org/content/early/2021/02/15/2159-8290.CD-20-0812.full.pdf},
interhash = {c71a5877420508bfb17d70177b99798a},
intrahash = {6e1a6a8885424e4d3da5d72a3bad96a3},
issn = {2159-8274},
journal = {Cancer Discovery},
keywords = {Class I MHC PD-l1 TRAF3 antigen checkpoint immuno-oncology myown presentation},
publisher = {American Association for Cancer Research},
timestamp = {2021-02-18T19:03:25.000+0100},
title = {Therapeutically increasing MHC-I expression potentiates immune checkpoint blockade},
url = {https://cancerdiscovery.aacrjournals.org/content/early/2021/02/15/2159-8290.CD-20-0812},
year = 2021
}