Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression.

Autor: Cheung PF; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Yang J; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Fang R; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Borgers A; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Krengel K; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Stoffel A; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Althoff K; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Yip CW; Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan., Siu EHL; Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China., Ng LWC; Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China., Lang KS; Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany., Cham LB; Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany., Engel DR; Department of Immunodynamics, Institute of Experimental Immunology and Imaging, University Hospital Essen, Essen, Germany., Soun C; Department of Immunodynamics, Institute of Experimental Immunology and Imaging, University Hospital Essen, Essen, Germany., Cima I; DKFZ-Division Translational Neurooncology at the WTZ, German Cancer Consortium (DKTK partner site Essen/Düsseldorf), Essen, Germany., Scheffler B; DKFZ-Division Translational Neurooncology at the WTZ, German Cancer Consortium (DKTK partner site Essen/Düsseldorf), Essen, Germany., Striefler JK; Universitätsmedizin Charité Berlin, CONKO Study Group, Department of Medical Oncology, Haematology and Tumorimmunology, Berlin, Germany., Sinn M; Universitätsmedizin Charité Berlin, CONKO Study Group, Department of Medical Oncology, Haematology and Tumorimmunology, Berlin, Germany., Bahra M; Department of Surgical Oncology and Robotics, Krankenhaus Waldfriede, Berlin, Germany., Pelzer U; Medical Department, Division of Hematology, Oncology and Tumor Immunology, Charité University Hospital, Berlin, Germany., Oettle H; Praxis und Tagesklinik, Dresden, Germany., Markus P; Department of General, Visceral and Trauma Surgery, Elisabeth Hospital Essen, Essen, Germany., Smeets EMM; Department of Medical Imaging, Radboud university medical Center, Nijmegen, The Netherlands., Aarntzen EHJG; Department of Medical Imaging, Radboud university medical Center, Nijmegen, The Netherlands., Savvatakis K; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Liffers ST; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Lueong SS; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Neander C; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Bazarna A; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Zhang X; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Paschen A; Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Crawford HC; Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA., Chan AWH; Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China., Cheung ST; Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China. stcheung@surgery.cuhk.edu.hk.; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China. stcheung@surgery.cuhk.edu.hk., Siveke JT; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany. j.siveke@dkfz.de.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. j.siveke@dkfz.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Jan 10; Vol. 13 (1), pp. 156. Date of Electronic Publication: 2022 Jan 10.
DOI: 10.1038/s41467-021-27088-9
Abstrakt: Immune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not fully known. Here, we characterize the function of tumor-derived PGRN in promoting immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN is associated with poor overall survival in PDAC. Multiplex immunohistochemistry shows low MHC class I (MHCI) expression and lack of CD8 + T cell infiltration in PGRN-high tumors. Inhibition of PGRN abrogates autophagy-dependent MHCI degradation and restores MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a PDAC mouse model remarkably decelerates tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as a model antigen are sensitized to gp33-TCR transgenic T cell-mediated cytotoxicity upon PGRN blockade. Overall, our study shows a crucial function of tumor-derived PGRN in regulating immunogenicity of primary PDAC.
(© 2022. The Author(s).)
Databáze: MEDLINE
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