ABSTRACT
Immune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain elusive. Here, we unveiled a cancer cell-autonomous function of PGRN in driving immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN was associated with poor overall survival in PDAC. Multiplex immunohistochemistry revealed low MHC class I (MHCI) expression and lack of CD8+ T cells infiltration in PGRN-high tumors. Inhibition of PGRN abrogated autophagy-dependent MHCI degradation and restored MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a genetic PDAC mouse model remarkably decelerated tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as model antigen were sensitized towards cytotoxic gp33-TCR transgenic T cells upon anti-PGRN antibody treatment. Overall, our study uncovered an unprecedented role of tumor-derived PGRN in regulating immunogenicity of primary PDAC.
STATEMENT OF SIGNIFICANCE Immune evasion is a key property of PDAC, rendering it refractory to immunotherapy. Here we demonstrate that tumor-derived PGRN promotes autophagy-dependent MHCI degradation, while anti-PGRN increases intratumoral CD8 infiltration and blocks tumor progression. With recent advances in T cell-mediated approaches, PGRN represents a pivotal target to enhance tumor antigen-specific cytotoxicity.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
FINANCIAL SUPPORT: P.F. Cheung has received funding from the Deutsche Forschungsgemeinschaft (DFG) for this study (CH 2320/2-3). J.T. Siveke is supported by the German Cancer Consortium (DKTK), the Deutsche Forschungsgemeinschaft (DFG) through grant SI1549/3-1 (Clinical Research Unit KFO337) and through the Collaborative Research Center SFB824 (project C4), and the German Cancer Aid (grant no. 70112505; PIPAC consortium). S.T. Cheung is supported by the Health and Medical Research Fund (05160556). E.H.J.G. Aarntzen received funding from Radboud Oncology Fund/Bergh in het Zadel (KUN2016-8106) and Radboud Oncology Fund/Barghse Jongens (ROF1817). We thank Dr. T. Ebel (Zentrum f. Pathologie Essen-Mitte) for kind support.
CONFLICT OF INTEREST DISCLOSURE STATEMENT: The authors declare no competing financial interests.
