Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators

Jiakai Hou, Yunfei Wang, Leilei Shi, Yuan Chen, Chunyu Xu, Arash Saeedi, Ke Pan, Ritu Bohat, Nicholas A. Egan, Jodi A. McKenzie, Rina M. Mbofung, Leila J. Williams, Zhenhuang Yang, Ming Sun, Xiaofang Liang, Jordi Rodon Ahnert, Navin Varadarajan, Cassian Yee, Yiwen Chen, Patrick HwuWeiyi Peng

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Background Despite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer. Methods To identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in an unbiased manner, we performed genome-wide CRISPR immune screens and integrated our results with multi-omics clinical data to evaluate the role of tumor intrinsic factors in regulating two rate-limiting steps of cancer immunotherapy, namely, T cell tumor infiltration and T cell-mediated tumor killing. Results Our studies revealed two distinct types of immune resistance regulators and demonstrated their potential as therapeutic targets to improve the efficacy of immunotherapy. Among them, PRMT1 and RIPK1 were identified as a dual immune resistance regulator and a cytotoxicity resistance regulator, respectively. Although the magnitude varied between different types of immunotherapy, genetically targeting PRMT1 and RIPK1 sensitized tumors to T-cell killing and anti-PD-1/OX40 treatment. Interestingly, a RIPK1-specific inhibitor enhanced the antitumor activity of T cell-based and anti-OX40 therapy, despite limited impact on T cell tumor infiltration. Conclusions Collectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations.

Original languageEnglish (US)
Article numbere001819
JournalJournal for immunotherapy of cancer
Volume9
Issue number2
DOIs
StatePublished - Feb 15 2021

Keywords

  • Immunotherapy
  • Tumor microenvironment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

MD Anderson CCSG core facilities

  • Flow Cytometry and Cellular Imaging Facility
  • Advanced Technology Genomics Core

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