Unconventional human CD61 pairing with CD103 promotes TCR signaling and antigen-specific T cell cytotoxicity

作者全名："Hamid, Megat H. B. A.; Cespedes, Pablo F.; Jin, Chen; Chen, Ji-Li; Gileadi, Uzi; Antoun, Elie; Liang, Zhu; Gao, Fei; Teague, Renuka; Manoharan, Nikita; Maldonado-Perez, David; Khalid-Alham, Nasullah; Cerundolo, Lucia; Ciaoca, Raul; Hester, Svenja S.; Pinto-Fernandez, Adan; Draganov, Simeon D.; Vendrell, Iolanda; Liu, Guihai; Yao, Xuan; Kvalvaag, Audun; Dominey-Foy, Delaney C. C.; Nanayakkara, Charunya; Kanellakis, Nikolaos; Chen, Yi-Ling; Waugh, Craig; Clark, Sally-Ann; Clark, Kevin; Sopp, Paul; Rahman, Najib M.; Verrill, Clare; Kessler, Benedikt M.; Ogg, Graham; Fernandes, Ricardo A.; Fisher, Roman; Peng, Yanchun; Dustin, Michael L.; Dong, Tao"

作者地址："[Hamid, Megat H. B. A.; Cespedes, Pablo F.; Jin, Chen; Chen, Ji-Li; Antoun, Elie; Liang, Zhu; Gao, Fei; Teague, Renuka; Manoharan, Nikita; Maldonado-Perez, David; Ciaoca, Raul; Pinto-Fernandez, Adan; Draganov, Simeon D.; Vendrell, Iolanda; Liu, Guihai; Yao, Xuan; Dominey-Foy, Delaney C. C.; Nanayakkara, Charunya; Kanellakis, Nikolaos; Chen, Yi-Ling; Rahman, Najib M.; Verrill, Clare; Kessler, Benedikt M.; Ogg, Graham; Fernandes, Ricardo A.; Fisher, Roman; Peng, Yanchun; Dustin, Michael L.; Dong, Tao] Univ Oxford, CAMS Oxford Inst, Nuffield Dept Med, Oxford, England; [Cespedes, Pablo F.; Kvalvaag, Audun; Dustin, Michael L.] Univ Oxford, Kennedy Inst Rheumatol, Oxford, England; [Jin, Chen] Chongqing Med Univ, Dept Cardiothorac Surg, Affiliated Hosp 1, Chongqing, Peoples R China; [Chen, Ji-Li; Gileadi, Uzi; Chen, Yi-Ling; Ogg, Graham; Peng, Yanchun; Dong, Tao] Univ Oxford, MRC Weatherall Inst Mol Med, Radcliffe Dept Med, MRC Translat Immune Discovery Unity, Oxford, England; [Antoun, Elie] Univ Oxford, Ctr Human Genet, Nuffield Dept Med, Oxford, England; [Liang, Zhu; Hester, Svenja S.; Pinto-Fernandez, Adan; Draganov, Simeon D.; Vendrell, Iolanda; Kessler, Benedikt M.; Fisher, Roman] Univ Oxford, Target Discovery Inst, Ctr Med Discovery, Oxford, England; [Teague, Renuka; Maldonado-Perez, David; Cerundolo, Lucia; Verrill, Clare] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England; [Khalid-Alham, Nasullah] Univ Oxford, Inst Biomed Engn, Dept Engn Sci, Oxford, England; [Khalid-Alham, Nasullah; Kanellakis, Nikolaos; Rahman, Najib M.; Verrill, Clare] John Radcliffe Hosp, Oxford Natl Inst Hlth Res NIHR, Biomed Res Ctr, Oxford, England; [Kvalvaag, Audun] Oslo Univ Hosp, Inst Canc Res, Dept Mol Cell Biol, Oslo, Norway; [Kanellakis, Nikolaos; Rahman, Najib M.] Univ Oxford, Nuffield Dept Med, Lab Pleural & Lung Canc Translat Res, Oxford, England; [Kanellakis, Nikolaos; Rahman, Najib M.] Oxford Univ Hosp, Churchill Hosp, Oxford Ctr Resp Med, Oxford, England; [Waugh, Craig; Clark, Sally-Ann; Clark, Kevin; Sopp, Paul] Univ Oxford, MRC Weatherall Inst Mol Med, Radcliffe Dept Med, Flow Cytometry Facil, Oxford, England"

通信作者："Dong, T (通讯作者)，Univ Oxford, CAMS Oxford Inst, Nuffield Dept Med, Oxford, England.; Dong, T (通讯作者)，Univ Oxford, MRC Weatherall Inst Mol Med, Radcliffe Dept Med, MRC Translat Immune Discovery Unity, Oxford, England."

来源：NATURE IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001194904500001

JCR分区：Q1

影响因子：27.7

年份：2024

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：　

摘要："Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies. CD103+ T cells are associated with control over tumors but how this is mediated is unclear. Here the authors show that CD61 colocalizes and functionally combines with CD103 in the T cell synaptic response to promote antitumor T cell responses."

基金机构："Chinese Academy of Medical Sciences (CAMS); University of Oxford; Oxford CRUK Cancer Centre [2018-I2M-002]; Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CFMS), China; UK MRC; CAMS Oxford Institute (COI) Career Development Fellowship; NIHR Biomedical Research Centre [SYNECT AdG 670930]; ERC Advanced Grant; Kennedy Trust for Rheumatology Research [ALTF 1420-2015]; EMBO Long-Term Fellowship [LTFCOFUND2013 GA-2013-609409]; European Commission; Oxford-Bristol Myers Squibb Fellowship"

基金资助正文："We thank patients who volunteered to participate in this study. We express our gratitude to the late S. Ling Felce (CAMS Oxford Institute, University of Oxford) for the bioinformatics contribution to this study. We thank G. Zavalani (ORB, Nuffield Department of Surgical Sciences, University of Oxford) for assisting in patient acquisition and sampling during the early stage of this study, and A. Hayes and D. Royston (John Radcliffe Hospital, NHS Oxford University Hospitals) for assisting in the initial tumor sampling, preparation and immunohistochemistry staining. We thank X. Yang (CAMS Oxford Institute, University of Oxford) for the assistance with the functional assay work on the seven paired T cell lines. We thank J. Forbester (Cardiff University) for advice on knock-down system. We thank V. Junghans (CAMS Oxford Institute, University of Oxford) for providing initial guidance to R.C. for the plasmids making and preparation. Figure 3h was created with BioRender.com. We acknowledge the contribution to this study made by the Oxford Centre for Histopathology Research and the ORB, which are supported by the University of Oxford, the Oxford CRUK Cancer Centre and the NIHR Oxford Biomedical Research Centre (Molecular Diagnostics Theme/Multimodal Pathology Subtheme), and the NIHR CRN Thames Valley Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the UK Department of Health. This work is supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CFMS), China (grant no. 2018-I2M-002 to T.D., M.H.B.A.H., P.F.C., C.J., Z.L., E.A., F.G., R.T., D.M-P., J-L.C., R.C., A.P.F., I.V., S.D., G.L., X.Y., N.M., N.K., D.C.C.D-F., Y-L.C., N.M.R., B.M.K., C.V., G.O., R.A.F., R.F., Y.P. and M.L.D.), UK MRC (T.D., Y.P., G.O. and J.-L.C.), CAMS Oxford Institute (COI) Career Development Fellowship (P.F.C., A.P.F., N.I.K. and Y.-L.C.). A.P.F. and S.D. are supported by Pfizer funding. Further support was provided from the NIHR Biomedical Research Centre (N.K.-A, C.V. and G.O.), Senior Investigator Award (G.O.) and Clinical Research Network (G.O.). M.L.D. was additionally supported by an ERC Advanced Grant (SYNECT AdG 670930) and the Kennedy Trust for Rheumatology Research. P.F.C. was supported by EMBO Long-Term Fellowship ALTF 1420-2015, in conjunction with the European Commission (LTFCOFUND2013 GA-2013-609409) Marie Sklodowska-Curie Actions and a Oxford-Bristol Myers Squibb Fellowship."