Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators
| Autor: | Rina M. Mbofung, Yunfei Wang, Xiaofang Liang, Nicholas A. Egan, Arash Saeedi, P. Hwu, Cassian Yee, Leila Williams, Navin Varadarajan, Yuan Chen, Weiyi Peng, Zhenhuang Yang, Jodi A. McKenzie, Ke Pan, Ming Sun, Jiakai Hou, Chunyu Xu, Yiwen Chen, Jordi Rodon Ahnert, Leilei Shi, Ritu Bohat |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cytotoxicity Immunologic Cancer Research Protein-Arginine N-Methyltransferases medicine.medical_treatment T cell T-Lymphocytes Immunology Regulator Mice Transgenic Biology 03 medical and health sciences 0302 clinical medicine Immune system Lymphocytes Tumor-Infiltrating Cancer immunotherapy Cell Line Tumor Neoplasms medicine Tumor Microenvironment Immunology and Allergy CRISPR Animals Humans Immune Checkpoint Inhibitors RC254-282 Pharmacology Tumor microenvironment Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cancer Basic Tumor Immunology Immunotherapy Genomics medicine.disease Mice Inbred C57BL Repressor Proteins 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Receptor-Interacting Protein Serine-Threonine Kinases Cancer research Molecular Medicine Tumor Escape immunotherapy CRISPR-Cas Systems |
| Zdroj: | Journal for Immunotherapy of Cancer Journal for ImmunoTherapy of Cancer, Vol 9, Iss 2 (2021) |
| ISSN: | 2051-1426 |
| Popis: | 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 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.ConclusionsCollectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations. |
| Databáze: | OpenAIRE |
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