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

• DOI: 10.1136/jitc-2020-001819
• Publication Date: 2021-02-15T23:22:52Z
• Authors: 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 Hwu; Weiyi Peng
• Keywords: Cytotoxicity, Immunologic; 0301 basic medicine; Protein-Arginine N-Methyltransferases; T-Lymphocytes; Mice, Transgenic; Mice; 03 medical and health sciences; Lymphocytes, Tumor-Infiltrating; Cell Line, Tumor; Neoplasms; Tumor Microenvironment; Animals; Humans; Immune Checkpoint Inhibitors; RC254-282; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Basic Tumor Immunology; Genomics; 3. Good health; Mice, Inbred C57BL; Repressor Proteins; Receptor-Interacting Protein Serine-Threonine Kinases; Tumor Escape; Immunotherapy; CRISPR-Cas Systems

BackgroundDespite 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.MethodsTo 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.ResultsOur 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 targetingPRMT1andRIPK1sensitized 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.ConclusionsCollectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations.