FAK promotes stromal PD-L2 expression associated with poor survival in pancreatic cancer

Catherine Davidson; David Taggart; Andrew H Sims; David W Lonergan; Marta Canel; Alan Serrels

doi:10.1038/s41416-022-01966-5

FAK promotes stromal PD-L2 expression associated with poor survival in pancreatic cancer

Catherine Davidson
, David Taggart
, Andrew H Sims
, David W Lonergan
, Marta Canel
, Alan Serrels^*

^*Corresponding author for this work

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

Abstract

Background

Pancreatic Cancer is one of the most lethal cancers, with less than 8% of patients surviving 5 years following diagnosis. The last 40 years have seen only small incremental improvements in treatment options, highlighting the continued need to better define the cellular and molecular pathways contributing to therapy response and patient prognosis.

Methods

We combined CRISPR, shRNA and flow cytometry with mechanistic experiments using a KrasG12Dp53R172H mouse model of pancreatic cancer and analysis of publicly available human PDAC transcriptomic datasets.

Results

Here, we identify that expression of the immune checkpoint, Programmed Death Ligand 2 (PD-L2), is associated with poor prognosis, tumour grade, clinical stage and molecular subtype in patients with Pancreatic Ductal Adenocarcinoma (PDAC). We further show that PD-L2 is predominantly expressed in the stroma and, using an orthotopic murine model of PDAC, identify cancer cell-intrinsic Focal Adhesion Kinase (FAK) signalling as a regulator of PD-L2 stromal expression. Mechanistically, we find that FAK regulates interleukin-6, which can act in concert with interleukin-4 secreted by CD4 T-cells to drive elevated expression of PD-L2 on tumour-associated macrophages, dendritic cells and endothelial cells.

Conclusions

These findings identify further complex heterocellular signalling networks contributing to FAK-mediated immune suppression in pancreatic cancer.

Original language	English
Journal	British Journal of Cancer
Early online date	22 Sept 2022
DOIs	https://doi.org/10.1038/s41416-022-01966-5
Publication status	E-pub ahead of print - 22 Sept 2022

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Cite this

@article{6ae817f01ad34c188991ffa49d3d78af,

title = "FAK promotes stromal PD-L2 expression associated with poor survival in pancreatic cancer",

abstract = "Background Pancreatic Cancer is one of the most lethal cancers, with less than 8\% of patients surviving 5 years following diagnosis. The last 40 years have seen only small incremental improvements in treatment options, highlighting the continued need to better define the cellular and molecular pathways contributing to therapy response and patient prognosis. Methods We combined CRISPR, shRNA and flow cytometry with mechanistic experiments using a KrasG12Dp53R172H mouse model of pancreatic cancer and analysis of publicly available human PDAC transcriptomic datasets. Results Here, we identify that expression of the immune checkpoint, Programmed Death Ligand 2 (PD-L2), is associated with poor prognosis, tumour grade, clinical stage and molecular subtype in patients with Pancreatic Ductal Adenocarcinoma (PDAC). We further show that PD-L2 is predominantly expressed in the stroma and, using an orthotopic murine model of PDAC, identify cancer cell-intrinsic Focal Adhesion Kinase (FAK) signalling as a regulator of PD-L2 stromal expression. Mechanistically, we find that FAK regulates interleukin-6, which can act in concert with interleukin-4 secreted by CD4 T-cells to drive elevated expression of PD-L2 on tumour-associated macrophages, dendritic cells and endothelial cells. Conclusions These findings identify further complex heterocellular signalling networks contributing to FAK-mediated immune suppression in pancreatic cancer.",

author = "Catherine Davidson and David Taggart and Sims, \{Andrew H\} and Lonergan, \{David W\} and Marta Canel and Alan Serrels",

note = "Funding Information: This work was supported by Cancer Research UK (Grant no. C39669/A25919 to AS). CD was supported by a Wellcome Trust Research Training Fellowship (Grant no. 109888/Z/15/Z). DT was supported by a Cancer Research UK Immunology Award (Grant no. C54352/A22011 awarded to Stephen M. Anderton and AS). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = sep,

day = "22",

doi = "10.1038/s41416-022-01966-5",

language = "English",

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T1 - FAK promotes stromal PD-L2 expression associated with poor survival in pancreatic cancer

AU - Davidson, Catherine

AU - Taggart, David

AU - Sims, Andrew H

AU - Lonergan, David W

AU - Canel, Marta

AU - Serrels, Alan

N1 - Funding Information: This work was supported by Cancer Research UK (Grant no. C39669/A25919 to AS). CD was supported by a Wellcome Trust Research Training Fellowship (Grant no. 109888/Z/15/Z). DT was supported by a Cancer Research UK Immunology Award (Grant no. C54352/A22011 awarded to Stephen M. Anderton and AS). Publisher Copyright: © 2022, The Author(s).

PY - 2022/9/22

Y1 - 2022/9/22

N2 - Background Pancreatic Cancer is one of the most lethal cancers, with less than 8% of patients surviving 5 years following diagnosis. The last 40 years have seen only small incremental improvements in treatment options, highlighting the continued need to better define the cellular and molecular pathways contributing to therapy response and patient prognosis. Methods We combined CRISPR, shRNA and flow cytometry with mechanistic experiments using a KrasG12Dp53R172H mouse model of pancreatic cancer and analysis of publicly available human PDAC transcriptomic datasets. Results Here, we identify that expression of the immune checkpoint, Programmed Death Ligand 2 (PD-L2), is associated with poor prognosis, tumour grade, clinical stage and molecular subtype in patients with Pancreatic Ductal Adenocarcinoma (PDAC). We further show that PD-L2 is predominantly expressed in the stroma and, using an orthotopic murine model of PDAC, identify cancer cell-intrinsic Focal Adhesion Kinase (FAK) signalling as a regulator of PD-L2 stromal expression. Mechanistically, we find that FAK regulates interleukin-6, which can act in concert with interleukin-4 secreted by CD4 T-cells to drive elevated expression of PD-L2 on tumour-associated macrophages, dendritic cells and endothelial cells. Conclusions These findings identify further complex heterocellular signalling networks contributing to FAK-mediated immune suppression in pancreatic cancer.

AB - Background Pancreatic Cancer is one of the most lethal cancers, with less than 8% of patients surviving 5 years following diagnosis. The last 40 years have seen only small incremental improvements in treatment options, highlighting the continued need to better define the cellular and molecular pathways contributing to therapy response and patient prognosis. Methods We combined CRISPR, shRNA and flow cytometry with mechanistic experiments using a KrasG12Dp53R172H mouse model of pancreatic cancer and analysis of publicly available human PDAC transcriptomic datasets. Results Here, we identify that expression of the immune checkpoint, Programmed Death Ligand 2 (PD-L2), is associated with poor prognosis, tumour grade, clinical stage and molecular subtype in patients with Pancreatic Ductal Adenocarcinoma (PDAC). We further show that PD-L2 is predominantly expressed in the stroma and, using an orthotopic murine model of PDAC, identify cancer cell-intrinsic Focal Adhesion Kinase (FAK) signalling as a regulator of PD-L2 stromal expression. Mechanistically, we find that FAK regulates interleukin-6, which can act in concert with interleukin-4 secreted by CD4 T-cells to drive elevated expression of PD-L2 on tumour-associated macrophages, dendritic cells and endothelial cells. Conclusions These findings identify further complex heterocellular signalling networks contributing to FAK-mediated immune suppression in pancreatic cancer.

U2 - 10.1038/s41416-022-01966-5

DO - 10.1038/s41416-022-01966-5

M3 - Article

SN - 0007-0920

JO - British Journal of Cancer

JF - British Journal of Cancer

ER -

FAK promotes stromal PD-L2 expression associated with poor survival in pancreatic cancer

Abstract

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