首页|Continuous Expression of Interferon Regulatory Factor 4 Sustains CD8+T Cell Immunity against Tumor

Continuous Expression of Interferon Regulatory Factor 4 Sustains CD8+T Cell Immunity against Tumor

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T-cell-based immunotherapy is gaining momentum in cancer treatment;however,our comprehension of the transcriptional regulation governing T cell antitumor activity remains constrained.The objective of this study was to explore the function of interferon regulatory factor 4(IRF4)in antitumor CD8+T cells using the TRAMP-C1 prostate cancer and B16F10 melanoma model.To achieve this,we generated an Irf4GFPDTR mouse strain and discovered that CD8+tumor-infiltrating lymphocytes(TILs)expressing high levels of IRF4.GFP exhibited a more differentiated PD-1high cell phenotype.By administering diphtheria toxin to tumor-bearing Irf4GFP-DTR mice,we partially depleted IRF4.GFP+TILs and observed an accelerated tumor growth.To specifically explore the function of IRF4 in antitumor CD8+T cells,we conducted 3 adoptive cell therapy(ACT)models.Firstly,depleting IRF4.GFP+CD8+TILs derived from ACT significantly accelerated tumor growth,emphasizing their crucial role in controlling tumor progression.Secondly,deleting the Irf4 gene in antitumor CD8+T cells used for ACT led to a reduction in the frequency and effector differentiation of CD8+TILs,completely abolishing the antitumor effects of ACT.Lastly,we performed a temporal deletion of the Irf4 gene in antitumor CD8+T cells during ACT,starting from 20 days after tumor implantation,which significantly compromised tumor control.Therefore,sustained expression of IRF4 is essential for maintaining CD8+T cell immunity in the melanoma model,and these findings carry noteworthy implications for the advancement of more potent immunotherapies for solid tumors.

Anze Yu、Jinfei Fu、Zheng Yin、Hui Yan、Xiang Xiao、Dawei Zou、Xiaolong Zhang、Xiongbing Zu、Xian C.Li、Wenhao Chen

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Immunobiology and Transplant Science Center,Department of Surgery,Houston Methodist Research Institute and Institute for Academic Medicine,Houston Methodist Hospital,Houston,TX,USA

Department of Urology,First Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong,China

Systems Medicine and Bioengineering Department,Houston Methodist Neal Cancer Center,Houston,TX,USA

Department of Radiology,Houston Methodist Hospital,Weill Cornell Medicine,Houston,TX,USA

Department of Urology,Xiangya Hospital,Central South University,Changsha,Hunan,China

Department of Surgery,Weill Cornell Medicine,Cornell University,New York,NY,USA

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2024

10.34133/research.0271

研究(英文)

研究(英文)

CSTPCD
ISSN：
年,卷(期)：2024.2024(3)