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

被引：48

作者：

Cheung, Phyllis F. ^{[1
,2
,3
]}

Yang, JiaJin ^{[1
,2
,3
]}

Fang, Rui ^{[1
,2
,3
]}

Borgers, Arianna ^{[1
,2
,3
]}

Krengel, Kirsten ^{[1
,2
,3
]}

Stoffel, Anne ^{[1
,2
,3
]}

Althoff, Kristina ^{[1
,2
,3
]}

Yip, Chi Wai ^{[4
,5
]}

Siu, Elaine H. L. ^{[4
]}

Ng, Linda W. C. ^{[4
]}

Lang, Karl S. ^{[6
]}

Cham, Lamin B. ^{[6
]}

Engel, Daniel R. ^{[7
]}

Soun, Camille ^{[7
]}

Cima, Igor ^{[8
]}

Scheffler, Bjoern ^{[8
]}

Striefler, Jana K. ^{[9
]}

Sinn, Marianne ^{[9
]}

Bahra, Marcus ^{[10
]}

Pelzer, Uwe ^{[11
]}

Oettle, Helmut ^{[12
]}

Markus, Peter ^{[13
]}

Smeets, Esther M. M. ^{[14
]}

Aarntzen, Erik H. J. G. ^{[14
]}

Savvatakis, Konstantinos ^{[1
,2
,3
]}

Liffers, Sven-Thorsten ^{[1
,2
,3
]}

Lueong, Smiths S. ^{[1
,2
,3
]}

Neander, Christian ^{[1
,2
,3
]}

Bazarna, Anna ^{[1
,2
,3
]}

Zhang, Xin ^{[1
,2
,3
]}

Paschen, Annette ^{[15
]}

Crawford, Howard C. ^{[16
,17
]}

Chan, Anthony W. H. ^{[18
]}

Cheung, Siu Tim ^{[4
,19
]}

Siveke, Jens T. ^{[1
,2
,3
]}

机构：

[1] Univ Hosp Essen, Bridge Inst Expt Tumor Therapy, West German Canc Ctr, Essen, Germany

[2] German Canc Consortium DKTK, Div Solid Tumor Translat Oncol, Partner Site Essen, Heidelberg, Germany

[3] German Canc Res Ctr, DKFZ, Heidelberg, Germany

[4] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Surg, Hong Kong, Peoples R China

[5] RIKEN Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan

[6] Univ Duisburg Essen, Inst Immunol, Fac Med, Essen, Germany

[7] Univ Hosp Essen, Inst Expt Immunol & Imaging, Dept Immunodynam, Essen, Germany

[8] German Canc Consortium, DKFZ Div Translat Neurooncol, WTZ, DKTK Partner Site Essen Dusseldorf, Essen, Germany

[9] Univ Med Charite Berlin, Dept Med Oncol Haematol & Tumorimmunol, CONKO Study Grp, Berlin, Germany

[10] Krankenhaus Waldfriede, Dept Surg Oncol & Robot, Berlin, Germany

[11] Charite, Div Hematol Oncol & Tumor Immunol, Dept Med, Berlin, Germany

[12] Praxis & Tagesklin, Dresden, Germany

[13] Elisabeth Hosp Essen, Dept Gen Visceral & Trauma Surg, Essen, Germany

[14] Radboud Univ Nijmegen Med Ctr, Dept Med Imaging, Nijmegen, Netherlands

[15] Univ Duisburg Essen, Univ Hosp Essen, Dept Dermatol, Essen, Germany

[16] Univ Michigan, Rogel Comprehens Canc Ctr, Ann Arbor, MI USA

[17] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI USA

[18] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Anat & Cellular Pathol, Hong Kong, Peoples R China

[19] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Peoples R China

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

关键词：

D O I：

10.1038/s41467-021-27088-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：18

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