| Literature DB >> 33636129 |
Zeyu Chen1, Eri Arai2, Omar Khan3, Zhen Zhang4, Shin Foong Ngiow5, Yuan He6, Hua Huang7, Sasikanth Manne3, Zhendong Cao2, Amy E Baxter3, Zhangying Cai3, Elizabeth Freilich8, Mohammed A Ali3, Josephine R Giles3, Jennifer E Wu3, Allison R Greenplate3, Mohamed A Hakeem3, Qingzhou Chen2, Makoto Kurachi3, Kito Nzingha3, Viktoriya Ekshyyan3, Divij Mathew3, Zhuoyu Wen8, Nancy A Speck9, Alexis Battle10, Shelley L Berger4, E John Wherry11, Junwei Shi12.
Abstract
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.Entities:
Keywords: CD8; CRISPR; Fli1; cancer; chronic infection; effector CD8 T cell; exhausted CD8 T cell; exhaustion; immunotherapy; protective immunity
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Year: 2021 PMID： 33636129 PMCID： PMC8054351 DOI： 10.1016/j.cell.2021.02.019
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582