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

Phyllis F Cheung; JiaJin 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, JiaJin 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 PelzerHelmut 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^*

^*Corresponding author for this work

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

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
Publication status	Published - Dec 2022
Externally published	Yes

Keywords

Adenocarcinoma/genetics
Animals
Antibodies, Neutralizing/pharmacology
Antigens, Viral/genetics
Autophagy/drug effects
CD8-Positive T-Lymphocytes/drug effects
Carcinoma, Pancreatic Ductal/genetics
Cell Line, Tumor
Cell Movement/drug effects
Cohort Studies
Cytotoxicity, Immunologic
Gene Expression
Glycoproteins/genetics
Histocompatibility Antigens Class I/genetics
Humans
Lymphocytic choriomeningitis virus/genetics
Mice
Pancreatic Neoplasms/genetics
Peptide Fragments/genetics
Progranulins/antagonists & inhibitors
Proteolysis
Survival Analysis
Tumor Escape/genetics
Tumor Microenvironment/genetics
Viral Proteins/genetics
Xenograft Model Antitumor Assays

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10.1038/s41467-021-27088-9

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Cheung, P. F., Yang, 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{c3ce81b73fde4eb5a47719c62088289b,

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.",

keywords = "Adenocarcinoma/genetics, Animals, Antibodies, Neutralizing/pharmacology, Antigens, Viral/genetics, Autophagy/drug effects, CD8-Positive T-Lymphocytes/drug effects, Carcinoma, Pancreatic Ductal/genetics, Cell Line, Tumor, Cell Movement/drug effects, Cohort Studies, Cytotoxicity, Immunologic, Gene Expression, Glycoproteins/genetics, Histocompatibility Antigens Class I/genetics, Humans, Lymphocytic choriomeningitis virus/genetics, Mice, Pancreatic Neoplasms/genetics, Peptide Fragments/genetics, Progranulins/antagonists & inhibitors, Proteolysis, Survival Analysis, Tumor Escape/genetics, Tumor Microenvironment/genetics, Viral Proteins/genetics, Xenograft Model Antitumor Assays",

author = "Cheung, {Phyllis F} and JiaJin Yang 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 Sven-Thorsten Liffers 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 Publishing Group",

number = "1",

}

Cheung, PF, Yang, J, 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, S-T, 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, JiaJin

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.

KW - Adenocarcinoma/genetics

KW - Animals

KW - Antibodies, Neutralizing/pharmacology

KW - Antigens, Viral/genetics

KW - Autophagy/drug effects

KW - CD8-Positive T-Lymphocytes/drug effects

KW - Carcinoma, Pancreatic Ductal/genetics

KW - Cell Line, Tumor

KW - Cell Movement/drug effects

KW - Cohort Studies

KW - Cytotoxicity, Immunologic

KW - Gene Expression

KW - Glycoproteins/genetics

KW - Histocompatibility Antigens Class I/genetics

KW - Humans

KW - Lymphocytic choriomeningitis virus/genetics

KW - Mice

KW - Pancreatic Neoplasms/genetics

KW - Peptide Fragments/genetics

KW - Progranulins/antagonists & inhibitors

KW - Proteolysis

KW - Survival Analysis

KW - Tumor Escape/genetics

KW - Tumor Microenvironment/genetics

KW - Viral Proteins/genetics

KW - Xenograft Model Antitumor Assays

UR - http://www.scopus.com/inward/record.url?scp=85122850023&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-27088-9

DO - 10.1038/s41467-021-27088-9

M3 - Article

C2 - 35013174

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

Abstract

Keywords

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