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

J Immunother Cancer. 2021 Feb;9(2):e001819. doi: 10.1136/jitc-2020-001819.

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.

Keywords: immunotherapy; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CRISPR-Cas Systems*
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic / genetics
  • Genomics*
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunotherapy
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms / genetics*
  • Neoplasms / immunology
  • Neoplasms / therapy
  • Protein-Arginine N-Methyltransferases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Repressor Proteins / genetics
  • T-Lymphocytes / immunology
  • Tumor Escape / genetics*
  • Tumor Microenvironment / genetics*
  • Tumor Microenvironment / immunology

Substances

  • Immune Checkpoint Inhibitors
  • Repressor Proteins
  • PRMT1 protein, human
  • Prmt1 protein, mouse
  • Protein-Arginine N-Methyltransferases
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse