In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer.
Improving effector activity of antigen-specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (TEFF)-driving transcription factors (TFs), the transcriptional coordination of TEFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key mechanism restraining TEFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced TEFF responses without compromising memory or exhaustion precursors. Fli1 restrained TEFF 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 TEFF biology. CD8+ T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8+ T cell transcriptional landscape from excessive ETS:RUNX-driven TEFF cell differentiation. Moreover, genetic deletion of Fli1 improves TEFF differentiation and protective immunity in infections and cancer.
['Chen|Zeyu|Z|', 'Arai|Eri|E|', 'Khan|Omar|O|', 'Zhang|Zhen|Z|', 'Ngiow|Shin Foong|SF|', 'He|Yuan|Y|', 'Huang|Hua|H|', 'Manne|Sasikanth|S|', 'Cao|Zhendong|Z|', 'Baxter|Amy E|AE|', 'Cai|Zhangying|Z|', 'Freilich|Elizabeth|E|', 'Ali|Mohammed A|MA|', 'Giles|Josephine R|JR|', 'Wu|Jennifer E|JE|', 'Greenplate|Allison R|AR|', 'Hakeem|Mohamed A|MA|', 'Chen|Qingzhou|Q|', 'Kurachi|Makoto|M|', 'Nzingha|Kito|K|', 'Ekshyyan|Viktoriya|V|', 'Mathew|Divij|D|', 'Wen|Zhuoyu|Z|', 'Speck|Nancy A|NA|', 'Battle|Alexis|A|', 'Berger|Shelley L|SL|', 'Wherry|E John|EJ|', 'Shi|Junwei|J|']
D000818:Animals D018414:CD8-Positive T-Lymphocytes D064113:CRISPR-Cas Systems D002454:Cell Differentiation D002908:Chronic Disease D050677:Core Binding Factor Alpha 3 Subunit D044127:Epigenesis, Genetic D053263:Gene Regulatory Networks D007239:Infections D051379:Mice D009369:Neoplasms D051789:Proto-Oncogene Protein c-fli-1
CD8 CRISPR Fli1 cancer immunotherapy exhaustion protective immunity chronic infection effector CD8 T cell exhausted CD8 T cell