FAK suppresses antigen processing and presentation to promote immune evasion in pancreatic cancer

Marta Canel, Aleksandra Slawinska, David W. Lonergan, Ashwin Adrian Kallor, Rosie Upstill-Goddard, Catherine Davidson, Alex Von Kriegsheim, Andrew V. Biankin, Adam Byron, Javier Alfaro, Alan Serrels

Research output: Contribution to journalArticlepeer-review

Abstract

Objective Immunotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC) has shown limited efficacy. Poor CD8 T-cell infiltration, low neoantigen load and a highly immunosuppressive tumour microenvironment contribute to this lack of response. Here, we aimed to further investigate the immunoregulatory function of focal adhesion kinase (FAK) in PDAC, with specific emphasis on regulation of the type-II interferon response that is critical in promoting T-cell tumour recognition and effective immunosurveillance. Design We combined CRISPR, proteogenomics and transcriptomics with mechanistic experiments using a Kras G12D p53 R172H mouse model of pancreatic cancer and validated findings using proteomic analysis of human patient-derived PDAC cell lines and analysis of publicly available human PDAC transcriptomics datasets. Results Loss of PDAC cell-intrinsic FAK signalling promotes expression of the immunoproteasome and Major Histocompatibility Complex class-I (MHC-I), resulting in increased antigen diversity and antigen presentation by FAK-/- PDAC cells. Regulation of the immunoproteasome by FAK is a critical determinant of this response, optimising the physicochemical properties of the peptide repertoire for high affinity binding to MHC-I. Expression of these pathways can be further amplified in a STAT1-dependent manner via co-depletion of FAK and STAT3, resulting in extensive infiltration of tumour-reactive CD8 T-cells and further restraint of tumour growth. FAK-dependent regulation of antigen processing and presentation is conserved between mouse and human PDAC, but is lost in cells/tumours with an extreme squamous phenotype. Conclusion Therapies aimed at FAK degradation may unlock additional therapeutic benefit for the treatment of PDAC through increasing antigen diversity and promoting antigen presentation.

Original languageEnglish
Pages (from-to)131-155
Number of pages25
JournalGut
Volume73
Issue number1
Early online date28 Mar 2023
DOIs
Publication statusPublished - 7 Dec 2023

Keywords

  • Pancreatic Cancer
  • Immunology
  • Antigen Processing & Presentation
  • Neoantigens
  • Immunoproteasome
  • Focal Adhesion Kinase
  • cell adhesion molecules
  • pancreatic cancer
  • antigen presentation
  • immune response
  • antigen processing

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