Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity

Journal of Hematology & Oncology

Correspondence

Xiaoyu Zhou¹  Lei Peng¹  Paul Clark¹  Lupeng Ye¹  Adan Codina²  Jianjian Guo²  Jonathan J. Park³  Sidi Chen⁴  Stanley Lam⁵ 

[1] Department of Genetics, Yale University School of Medicine, New Haven, CT, USA;System Biology Institute, Yale University, West Haven, CI, USA;Center for Cancer Systems Biology, Yale University, West Haven, CI, USA;Department of Genetics, Yale University School of Medicine, New Haven, CT, USA;System Biology Institute, Yale University, West Haven, CI, USA;Center for Cancer Systems Biology, Yale University, West Haven, CI, USA;Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA;Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA;Department of Genetics, Yale University School of Medicine, New Haven, CT, USA;System Biology Institute, Yale University, West Haven, CI, USA;Center for Cancer Systems Biology, Yale University, West Haven, CI, USA;Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA;Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA;MD-PhD Program, Yale University, New Haven, CT, USA;Department of Genetics, Yale University School of Medicine, New Haven, CT, USA;System Biology Institute, Yale University, West Haven, CI, USA;Center for Cancer Systems Biology, Yale University, West Haven, CI, USA;Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA;Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA;MD-PhD Program, Yale University, New Haven, CT, USA;Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA;Immunobiology Program, Yale University, New Haven, CT, USA;Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA;Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA;Liver Center, Yale University School of Medicine, New Haven, CT, USA;Center for Biomedical Data Science, Yale University School of Medicine, New Haven, CT, USA;Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT, USA;Department of Genetics, Yale University School of Medicine, New Haven, CT, USA;System Biology Institute, Yale University, West Haven, CI, USA;Center for Cancer Systems Biology, Yale University, West Haven, CI, USA;The College, Yale University, New Haven, CT, USA;

关键词: CRISPR screen;    Immunotherapy;    Cancer immunology;    Genetic interaction;    Double knockout;    Systems biology;   

DOI  :  10.1186/s13045-022-01389-y

 received in 2022-08-18, accepted in 2022-11-22,  发布年份 2022

来源: Springer

【 摘 要 】

Immunotherapy has transformed cancer treatments; however, a large fraction of patients encounter resistance. Such resistance is mediated by complex factors, often involving interactions between multiple genes. Thus, it is crucially important to identify genetic interactions between genes that are significantly mutated in cancer patients and those involved in immune responses, ideally the ones that currently have chemical compounds for direct targeting. To systematically interrogate such genetic interactions that mediate cancer cells’ response to T cell killing, we designed an asymmetric dual perturbation library targeting the matched combinations between significantly mutated tumor suppressors and immune resistance genes. We performed a combinatorial double knockout screen on 1159 gene pairs and identified those where joint loss-of-function renders altered cellular response to T cell cytotoxicity. We also performed comparative transcriptomics-based analyses on tumor and normal samples from TCGA and GTEx cohorts, mutational profiling analyses, and survival analyses to further characterize the significance of identified hits in clinical patients. Interactions between significantly mutated tumor suppressors and potentially druggable immune resistance genes may offer insights on potential new concepts of how to target clinically relevant cancer mutations with currently available agents. This study also provides a technology platform and an asymmetric double knockout library for interrogating genetic interactions between cancer mutations and immune resistance pathways under various settings.

【 授权许可】

CC BY   
© The Author(s) 2022

【 图 表 】

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