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

Phyllis F. Cheung; Jia Jin Yang; Rui Fang; Arianna Borgers; Kirsten Krengel; Anne Stoffel; Kristina Althoff; Chi Wai Yip; Elaine H.L. Siu; Linda W.C. Ng; Karl S. Lang; Lamin B. Cham; Daniel R. Engel; Camille Soun; Igor Cima; Björn Scheffler; Jana K. Striefler; Marianne Sinn; Marcus Bahra; Uwe Pelzer; Helmut Oettle; Peter Markus; Esther M.M. Smeets; Erik H.J.G. Aarntzen; Konstantinos Savvatakis; Sven Thorsten Liffers; Smiths S. Lueong; Christian Neander; Anna Bazarna; Xin Zhang; Annette Paschen; Howard C. Crawford; Anthony W.H. Chan; Siu Tim Cheung; Jens T. Siveke

doi:10.1038/s41467-021-27088-9

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

Phyllis F. Cheung
, Jia Jin Yang
, Rui Fang
, Arianna Borgers
, Kirsten Krengel
, Anne Stoffel
, Kristina Althoff
, Chi Wai Yip
, Elaine H.L. Siu
, Linda W.C. Ng
, Karl S. Lang
, Lamin B. Cham
, Daniel R. Engel
, Camille Soun
, Igor Cima
, Björn Scheffler
, Jana K. Striefler
, Marianne Sinn
, Marcus Bahra
, Uwe Pelzer

Helmut Oettle, Peter Markus, Esther M.M. Smeets, Erik H.J.G. Aarntzen, Konstantinos Savvatakis, Sven Thorsten Liffers, Smiths S. Lueong, Christian Neander, Anna Bazarna, Xin Zhang, Annette Paschen, Howard C. Crawford, Anthony W.H. Chan, Siu Tim Cheung, Jens T. Siveke

University Hospital of Essen
German Cancer Research Center
Chinese University of Hong Kong
RIKEN Center for Integrative Medical Sciences
University Medicine Essen
Charité – Universitätsmedizin Berlin
Krankenhaus Waldfriede
Praxis und Tagesklinik
Elisabeth Krankenhaus Essen
Amalia Children's Hospital
University of Michigan
University of Michigan Medical School

Research output: Contribution to journal › Article › peer-review

68 Scopus citations

Abstract

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.

Original language	English
Article number	156
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-27088-9
State	Published - Dec 2022
Externally published	Yes

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SDG 3 Good Health and Well-being

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Cite this

Cheung, P. F., Yang, J. J., Fang, R., Borgers, A., Krengel, K., Stoffel, A., Althoff, K., Yip, C. W., Siu, E. H. L., Ng, L. W. C., Lang, K. S., Cham, L. B., Engel, D. R., Soun, C., Cima, I., Scheffler, B., Striefler, J. K., Sinn, M., Bahra, M., ... Siveke, J. T. (2022). Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression. Nature Communications, 13(1), Article 156. https://doi.org/10.1038/s41467-021-27088-9

@article{30720ff6ff77449190112f0687217657,

title = "Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression",

abstract = "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.",

author = "Cheung, \{Phyllis F.\} and Yang, \{Jia Jin\} and Rui Fang and Arianna Borgers and Kirsten Krengel and Anne Stoffel and Kristina Althoff and Yip, \{Chi Wai\} and Siu, \{Elaine H.L.\} and Ng, \{Linda W.C.\} and Lang, \{Karl S.\} and Cham, \{Lamin B.\} and Engel, \{Daniel R.\} and Camille Soun and Igor Cima and Bj{\"o}rn Scheffler and Striefler, \{Jana K.\} and Marianne Sinn and Marcus Bahra and Uwe Pelzer and Helmut Oettle and Peter Markus and Smeets, \{Esther M.M.\} and Aarntzen, \{Erik H.J.G.\} and Konstantinos Savvatakis and Liffers, \{Sven Thorsten\} and Lueong, \{Smiths S.\} and Christian Neander and Anna Bazarna and Xin Zhang and Annette Paschen and Crawford, \{Howard C.\} and Chan, \{Anthony W.H.\} and Cheung, \{Siu Tim\} and Siveke, \{Jens T.\}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-021-27088-9",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Cheung, PF, Yang, JJ, Fang, R, Borgers, A, Krengel, K, Stoffel, A, Althoff, K, Yip, CW, Siu, EHL, Ng, LWC, Lang, KS, Cham, LB, Engel, DR, Soun, C, Cima, I, Scheffler, B, Striefler, JK, Sinn, M, Bahra, M, Pelzer, U, Oettle, H, Markus, P, Smeets, EMM, Aarntzen, EHJG, Savvatakis, K, Liffers, ST, Lueong, SS, Neander, C, Bazarna, A, Zhang, X, Paschen, A, Crawford, HC, Chan, AWH, Cheung, ST & Siveke, JT 2022, 'Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression', Nature Communications, vol. 13, no. 1, 156. https://doi.org/10.1038/s41467-021-27088-9

TY - JOUR

T1 - Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression

AU - Cheung, Phyllis F.

AU - Yang, Jia Jin

AU - Fang, Rui

AU - Borgers, Arianna

AU - Krengel, Kirsten

AU - Stoffel, Anne

AU - Althoff, Kristina

AU - Yip, Chi Wai

AU - Siu, Elaine H.L.

AU - Ng, Linda W.C.

AU - Lang, Karl S.

AU - Cham, Lamin B.

AU - Engel, Daniel R.

AU - Soun, Camille

AU - Cima, Igor

AU - Scheffler, Björn

AU - Striefler, Jana K.

AU - Sinn, Marianne

AU - Bahra, Marcus

AU - Pelzer, Uwe

AU - Oettle, Helmut

AU - Markus, Peter

AU - Smeets, Esther M.M.

AU - Aarntzen, Erik H.J.G.

AU - Savvatakis, Konstantinos

AU - Liffers, Sven Thorsten

AU - Lueong, Smiths S.

AU - Neander, Christian

AU - Bazarna, Anna

AU - Zhang, Xin

AU - Paschen, Annette

AU - Crawford, Howard C.

AU - Chan, Anthony W.H.

AU - Cheung, Siu Tim

AU - Siveke, Jens T.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85122850023

U2 - 10.1038/s41467-021-27088-9

DO - 10.1038/s41467-021-27088-9

M3 - Article

C2 - 35013174

AN - SCOPUS:85122850023

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 156

ER -

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

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