(1) Zang H (2) Liu T (3) Wang X (4) Cheng S (5) Zhu X (6) Huang C (7) Duan L (8) Zhao X (9) Guo F (10) Wang X (11) Zhang C (12) Yang F (13) Gu Y (14) Hu H (15) Gao S

Journal for immunotherapy of cancer | Free PMC Article

Zang et al. found that due to alternative splicing events in tumors, an isoform of PDCD1 retaining the exon 2 PD-L1 binding domain and the second intron (PD-1IR2) was expressed in a variety of human leukemia cell lines, clinical tumor biopsies, and TILs. PD-1IR2 expression was induced upon T cell activation, and was regulated by the RNA-binding protein hnRNPLL. Like PD-1, PD-1IR2 inhibited CD8+ T cell proliferation, functionality, and tumor cell killing, allowing for increased tumor immune evasion. This suggested that PD-1IR2 acts as an immune checkpoint. Further, PD-1IR2 knock-in mice showed resistance to anti-PD-L1 compared with wild-type mice.

Contributed by Lauren Hitchings

BACKGROUND: The programmed cell death 1 (PD-1) is an immune checkpoint that mediates immune evasion of tumors. Alternative splicing (AS) such as intron retention (IR) plays a crucial role in the immune-related gene processing and its function. However, it is not clear whether PDCD1 encoding PD-1 exists as an IR splicing isoform and what underlying function of such isoform plays in tumor evasion. METHODS: An AS isoform of human PDCD1, characterized by the second IR and named PD-1(IR2), was identified by reverse transcription-PCR (RT-PCR) and Sanger sequencing. The expression profile of PD1(IR2) was assessed by quantitative RT-PCR and flow cytometry, while its function was evaluated through immune cell proliferation, cytokine interleukin 2 secretion, and tumor cell killing assays. PDCD1(IR2) (CKI) mice which specifically conditional knock-in PDCD1(IR2) in T cells and humanized peripheral blood mononuclear cells (PBMC)-NOG (NOD.Cg-PrkdcscidIL2rgtm1Sug/JicCrl) mice were utilized to further confirm the physiological function of PD-1(IR2) in vivo. RESULTS: PD-1(IR2) is expressed in a variety of human leukemia cell lines and tumor-infiltrating lymphocytes. PD-1(IR2) expression is induced on T cell activation and regulated by the RNA-binding protein hnRNPLL. PD-1(IR2) negatively regulates the immune function of CD8(+) T cells, indicated by inhibiting T cell proliferation, cytokine production, and tumor cell killing in vitro. PD-1(IR2+) CD8(+) T cells show impaired antitumor function, which consequently promote tumor evasion in a conditional knock-in mouse model and a PBMC-engrafted humanized NOG mouse model. PD-1(IR2) mice exhibit resistance to anti-PD-L1 therapy compared with wild-type mice. CONCLUSIONS: PD-1(IR2) is a potential immune checkpoint that may mediate potential resistance to immune checkpoint therapy.

Author Info: (1) Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China. Shanxi Academy of Advanced Research and Innovation, Taiyuan, Shanxi, China. (2) Sc

Author Info: (1) Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China. Shanxi Academy of Advanced Research and Innovation, Taiyuan, Shanxi, China. (2) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. Medical College, Guizhou University, Guiyang, Guizhou, China. (3) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. (4) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. Medical School of Nanjing University, Nanjing, Jiangsu, China. (5) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. Medical College, Guizhou University, Guiyang, Guizhou, China. (6) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. Medical College, Guizhou University, Guiyang, Guizhou, China. (7) Shanxi Academy of Advanced Research and Innovation, Taiyuan, Shanxi, China. School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. (8) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. (9) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, Shanxi, China. (10) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. (11) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. Department of oncology, The Key Laboratory of Advanced Interdisciplinary Studies, First Affiliated Hospital of Guangzhou Medical University State Key Laboratory of Respiratory Disease, Guangzhou, Guangdong, China. (12) School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China. (13) The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China gaos@sibet.ac.cn hongbohu@scu.edu.cn guym_81@126.com. School of Medicine, Southeast University, Nanjing, Jiangsu, China. (14) Center for Immunology and Hematology, Department of Biotherapy and Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China gaos@sibet.ac.cn hongbohu@scu.edu.cn guym_81@126.com. (15) Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China gaos@sibet.ac.cn hongbohu@scu.edu.cn guym_81@126.com. School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China.

Citation: J Immunother Cancer 2025 Mar 6 13: Epub03/06/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40050045

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