학술논문
In vivo CD8.sup.+ T cell CRISPR screening reveals control by Fli1 in infection and cancer
Document Type
Report
Author
Chen, Zeyu; Arai, Eri; Khan, Omar; Zhang, Zhen; Ngiow, Shin Foong; He, Yuan; Huang, Hua; Manne, Sasikanth; Cao, Zhendong; Baxter, Amy E.; Cai, Zhangying; Freilich, Elizabeth; Ali, Mohammed A.; Giles, Josephine R.; Wu, Jennifer E.; Greenplate, Allison R.; Hakeem, Mohamed A.; Chen, Qingzhou; Kurachi, Makoto; Nzingha, Kito; Ekshyyan, Viktoriya; Mathew, Divij; Wen, Zhuoyu; Speck, Nancy A.; Battle, Alexis; Berger, Shelley L.; Wherry, E. John; Shi, Junwei
Source
Cell. March 4, 2021, Vol. 184 Issue 5, 1262
Subject
Language
English
ISSN
0092-8674
Abstract
Keywords CRISPR; CD8; exhaustion; immunotherapy; Fli1; protective immunity; effector CD8 T cell; exhausted CD8 T cell; cancer; chronic infection Highlights * OpTICS In vivo CD8.sup.+ T cell CRISPR screening platform developed for focused gene discovery * OpTICS identifies genes involved in effector versus exhausted CD8.sup.+ T cells * The Fli1 transcription factor represses optimal effector CD8.sup.+ T cells during exhaustion * Fli1 antagonizes epigenetic accessibility at ETS-RUNX sites limiting Runx3 activity Summary Improving effector activity of antigen-specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (T.sub.EFF)-driving transcription factors (TFs), the transcriptional coordination of T.sub.EFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key mechanism restraining T.sub.EFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced T.sub.EFF responses without compromising memory or exhaustion precursors. Fli1 restrained T.sub.EFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs, allowing more efficient Runx3-driven T.sub.EFF biology. CD8.sup.+ T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8.sup.+ T cell transcriptional landscape from excessive ETS:RUNX-driven T.sub.EFF cell differentiation. Moreover, genetic deletion of Fli1 improves T.sub.EFF differentiation and protective immunity in infections and cancer.