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

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机构： [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]Affiliated Hospital of Hebei Engineering University, Handan, China. [7]Clinical Medical College, Hebei University of Engineering, Handan, China.

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Aging compromises antitumor immunity, but the underlying mechanisms remain elusive. Here, we report that aging impairs the generation of CD8+ tissue resident memory T (TRM) 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 TRM 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 TRM 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 TRM 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.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.

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大类 | 1 区

医学

小类 | 1 区细胞生物学 1 区老年医学 1 区神经科学

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无

最新[2023]版：

Q1 CELL BIOLOGY Q1 GERIATRICS & GERONTOLOGY Q1 NEUROSCIENCES

影响因子： 17 最新[2023版] 17 最新五年平均 0 出版当年[2024版] 0 出版当年五年平均 17 出版前一年[2023版]

第一作者：

第一作者机构： [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.

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通讯作者：

通讯机构： [4]Central Laboratory, Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Affiliated Hospital of Hebei University, Baoding, China. [6]Affiliated Hospital of Hebei Engineering University, Handan, China. [7]Clinical Medical College, Hebei University of Engineering, Handan, China.

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