The Transcription Factor Irf4 Determines The Anti-Tumor Immunity of CD8+ T Cells

Authors

Hui Yan
Yulin Dai
Xiaolong Zhang
Hedong Zhang
Xiang Xiao
Jinfei Fu
Dawei Zou
Anze Yu
Tao Jiang
Xian C Li
Zhongming Zhao
Wenhao Chen

Publication Date

11-17-2023

Journal

iScience

Abstract

Understanding the factors that regulate T cell infiltration and functional states in solid tumors is crucial for advancing cancer immunotherapies. Here, we discovered that the expression of interferon regulatory factor 4 (IRF4) was a critical T cell intrinsic requirement for effective anti-tumor immunity. Mice with T-cell-specific ablation of IRF4 showed significantly reduced T cell tumor infiltration and function, resulting in accelerated growth of subcutaneous syngeneic tumors and allowing the growth of allogeneic tumors. Additionally, engineered overexpression of IRF4 in anti-tumor CD8+ T cells that were adoptively transferred significantly promoted their tumor infiltration and transition from a naive/memory-like cell state into effector T cell states. As a result, IRF4-engineered anti-tumor T cells exhibited significantly improved anti-tumor efficacy, and inhibited tumor growth either alone or in combination with PD-L1 blockade. These findings identify IRF4 as a crucial cell-intrinsic driver of T cell infiltration and function in tumors, emphasizing the potential of IRF4-engineering as an immunotherapeutic approach.

Keywords

Molecular biology, Immunology, Cell biology, Cancer

Comments

Supplementary Materials

DOI

10.1016/j.isci.2023.108087

PMID

37860697

PMCID

PMC10583049

PubMedCentral® Posted Date

September 2023

PubMedCentral® Full Text Version

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