Age-related decline in CD8+ tissue resident memory T cells compromises antitumor immunity

Nat Aging. 2024 Dec;4(12):1828-1844. doi: 10.1038/s43587-024-00746-5.

Siyu Pei ^# ¹ ², Xiuyu Deng ^# ², Ruirui Yang ^# ³, Hui Wang ^# ¹, Jian-Hong Shi ^# ⁴, Xueqing Wang ², Jia Huang ¹, Yu Tian ¹, Rongjing Wang ², Sulin Zhang ³, Hui Hou ³, Jing Xu ², Qingcheng Zhu ², Huan Huang ², Jialing Ye ², Cong-Yi Wang ⁵, Wei Lu ², Qingquan Luo ⁶, Zhi-Yu Ni ⁷ ⁸ ⁹, Mingyue Zheng ¹⁰, Yichuan Xiao ¹¹

Affiliations

1 Department of Thoracic Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
3 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
4 Central Laboratory, Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Affiliated Hospital of Hebei University, Baoding, China.
5 Department of Respiratory and Critical Care Medicine, Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
6 Department of Thoracic Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. luoqingquan@hotmail.com.
7 Central Laboratory, Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Affiliated Hospital of Hebei University, Baoding, China. nizhiyu@hbu.edu.cn.
8 Affiliated Hospital of Hebei Engineering University, Handan, China. nizhiyu@hbu.edu.cn.
9 Clinical Medical College, Hebei University of Engineering, Handan, China. nizhiyu@hbu.edu.cn.
10 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. myzheng@simm.ac.cn.
11 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. ycxiao@sibs.ac.cn.
# Contributed equally.

PMID: 39592880 DOI: 10.1038/s43587-024-00746-5

Abstract

Aging compromises antitumor immunity, but the underlying mechanisms remain elusive. Here, we report that aging impairs the generation of CD8⁺ tissue resident memory T (T_RM) cells in nonlymphoid tissues in mice, thus compromising the antitumor activity of aged CD8⁺ T cells, which we also observed in human lung adenocarcinoma. We further identified that the Apoptosis regulator BFAR was highly enriched in aged CD8⁺ T cells, in which BFAR suppressed cytokine-induced JAK2 signaling by activating JAK2 deubiquitination, thereby limiting downstream STAT1-mediated T_RM reprogramming. Targeting BFAR either through Bfar knockout or treatment with our developed BFAR inhibitor, iBFAR2, rescued the antitumor activity of aged CD8⁺ T cells by restoring T_RM generation in the tumor microenvironment, thus efficiently inhibiting tumor growth in aged CD8⁺ T cell transfer and anti-programmed cell death protein 1 (PD-1)-resistant mouse tumor models. Together, our findings establish BFAR-induced T_RM restriction as a key mechanism causing aged CD8⁺ T cell dysfunction and highlight the translational potential of iBFAR2 in restoring antitumor activity in aged individuals or patients resistant to anti-PD-1 therapy.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-170393

iBFAR2

BFAR Inhibitor

JAK; STAT

Cancer

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