دورية أكاديمية
أعرض في EDS

Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer.

التفاصيل البيبلوغرافية
العنوان: Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer.
المؤلفون: Kuo WT; Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan., Kuo IY; Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan.; Department of Biotechnology, College of Biomedical Science, Kaohsiung Medical University, Kaohsiung, Taiwan., Hsieh HC; Institute of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Wu ST; Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan., Su WC; Division of Oncology, Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Wang YC; Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan. ycw5798@mail.ncku.edu.tw.; Institute of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. ycw5798@mail.ncku.edu.tw.
المصدر: Journal of biomedical science [J Biomed Sci] 2024 Feb 07; Vol. 31 (1), pp. 20. Date of Electronic Publication: 2024 Feb 07.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 9421567 Publication Model: Electronic Cited Medium: Internet ISSN: 1423-0127 (Electronic) Linking ISSN: 10217770 NLM ISO Abbreviation: J Biomed Sci Subsets: MEDLINE
أسماء مطبوعة: Publication: 2009- : London : BioMed Central
Original Publication: Basel ; New York : S. Karger Medical and Scientific Publishers, c1994-
مواضيع طبية MeSH: Lung Neoplasms*/pathology , Monomeric GTP-Binding Proteins*/metabolism, Animals ; Humans ; Mice ; CD8-Positive T-Lymphocytes/metabolism ; Hepatitis A Virus Cellular Receptor 2/metabolism ; Leukocytes, Mononuclear/metabolism ; Mice, Knockout ; Programmed Cell Death 1 Receptor ; rab GTP-Binding Proteins ; T-Cell Exhaustion ; Tumor Microenvironment
مستخلص: Background: Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor expressed on the surface of T cells. High expression of PD-1 leads to T-cell dysfunction in the tumor microenvironment (TME). However, the mechanism of intracellular trafficking and plasma membrane presentation of PD-1 remains unclear.
Methods: Multiple databases of lung cancer patients were integratively analyzed to screen Rab proteins and potential immune-related signaling pathways. Imaging and various biochemical assays were performed in Jurkat T cells, splenocytes, and human peripheral blood mononuclear cells (PBMCs). Rab37 knockout mice and specimens of lung cancer patients were used to validate the concept.
Results: Here, we identify novel mechanisms of intracellular trafficking and plasma membrane presentation of PD-1 mediated by Rab37 small GTPase to sustain T cell exhaustion, thereby leading to poor patient outcome. PD-1 colocalized with Rab37-specific vesicles of T cells in a GTP-dependent manner whereby Rab37 mediated dynamic trafficking and membrane presentation of PD-1. However, glycosylation mutant PD-1 delayed cargo recruitment to the Rab37 vesicles, thus stalling membrane presentation. Notably, T cell proliferation and activity were upregulated in tumor-infiltrating T cells from the tumor-bearing Rab37 knockout mice compared to those from wild type. Clinically, the multiplex immunofluorescence-immunohistochemical assay indicated that patients with high Rab37 + /PD-1 + /TIM3 + /CD8 + tumor infiltrating T cell profile correlated with advanced tumor stages and poor overall survival. Moreover, human PBMCs from patients demonstrated high expression of Rab37, which positively correlated with elevated levels of PD-1 + and TIM3 + in CD8 + T cells exhibiting reduced tumoricidal activity.
Conclusions: Our results provide the first evidence that Rab37 small GTPase mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion, and the tumor promoting function of Rab37/PD-1 axis in T cells of TME in lung cancer. The expression profile of Rab37 high /PD-1 high /TIM3 high in tumor-infiltrating CD8 + T cells is a biomarker for poor prognosis in lung cancer patients.
(© 2024. The Author(s).)
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معلومات مُعتمدة: MOST 106-2321-B-006-023 Ministry of Science and Technology, Taiwan; EX112-11212BI National Health Research Institute
فهرسة مساهمة: Keywords: Lung cancer; Membrane trafficking; PD-1; Rab37; T cell
المشرفين على المادة: 0 (Hepatitis A Virus Cellular Receptor 2)
EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
0 (Programmed Cell Death 1 Receptor)
EC 3.6.5.2 (rab GTP-Binding Proteins)
EC 3.6.1.- (Rab37 protein, human)
EC 3.6.1.- (Rab37 protein, mouse)
تواريخ الأحداث: Date Created: 20240206 Date Completed: 20240214 Latest Revision: 20240214
رمز التحديث: 20240214
مُعرف محوري في PubMed: PMC10848371
DOI: 10.1186/s12929-024-01009-6
PMID: 38321486
قاعدة البيانات: MEDLINE
الوصف
تدمد:1423-0127
DOI:10.1186/s12929-024-01009-6