Abstract IA11: T cell exclusion in pancreatic ductal adenocarcinoma: The FAP+ cancer-associated fibroblast and CXCL12

AbstractHow pancreatic ductal adenocarcinoma (PDA) cells stimulate CXCR4 to exclude T cells and resist T cell checkpoint inhibitors is not known. Here, we find that CXCL12, the ligand for CXCR4 that is produced by the cancer-associated fibroblast, “coats” human PDA and colorectal cancer cells as covalent heterodimers with keratin 19 (KRT19). Modeling the formation of the heterodimer with three proteins shows that KRT19 binds CXCL12 and transglutaminase-2 (TGM2), and that TGM2 converts the reversible KRT19-CXCL12 complex into a covalent heterodimer. We validate this model by showing that cancer cells in mouse PDA tumors must express KRT19 and TGM2 to become coated with CXCL12, exclude T cells, and resist immunotherapy with anti-PD-1 antibody. Thus, PDA cells have a cell-autonomous means by which they capture CXCL12 to mediate immune suppression, which is potentially amenable to therapy.One Sentence SummaryCancer cells in pancreatic ductal adenocarcinoma use transglutaminase-2 to assemble a coating comprised of covalent CXCL12-keratin 19 heterodimers that excludes T cells and mediates resistance to inhibition of the PD-1 T cell checkpoint.

Download Full-text

Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma

Scientific Reports ◽

10.1038/s41598-021-82937-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

J. I. Alexander ◽

D. B. Vendramini-Costa ◽

R. Francescone ◽

T. Luong ◽

J. Franco-Barraza ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Transforming Growth Factor ◽

Therapeutic Potential ◽

Ductal Adenocarcinoma ◽

Transforming Growth Factor Beta1 ◽

Cancer Associated Fibroblast ◽

Specific Tumor ◽

Immunosuppressive Microenvironment ◽

Anti Tumor Activity ◽

Immunosuppressive Cytokines

AbstractPancreatic Ductal Adenocarcinoma (PDAC) has a five-year survival under 10%. Treatment is compromised due to a fibrotic-like stromal remodeling process, known as desmoplasia, which limits therapeutic perfusion, supports tumor progression, and establishes an immunosuppressive microenvironment. These processes are driven by cancer-associated fibroblasts (CAFs), functionally activated through transforming growth factor beta1 (TGFβ1). CAFs produce a topographically aligned extracellular matrix (ECM) that correlates with reduced overall survival. Paradoxically, ablation of CAF populations results in a more aggressive disease, suggesting CAFs can also restrain PDAC progression. Thus, unraveling the mechanism(s) underlying CAF functions could lead to therapies that reinstate the tumor-suppressive features of the pancreatic stroma. CAF activation involves the f-actin organizing protein palladin. CAFs express two palladin isoforms (iso3 and iso4) which are up-regulated in response to TGFβ1. However, the roles of iso3 and iso4 in CAF functions remain elusive. Using a CAF-derived ECM model, we uncovered that iso3/iso4 are required to sustain TGFβ1-dependent CAF activation, secrete immunosuppressive cytokines, and produce a pro-tumoral ECM. Findings demonstrate a novel role for CAF palladin and suggest that iso3/iso4 regulate both redundant and specific tumor-supportive desmoplastic functions. This study highlights the therapeutic potential of targeting CAFs to restore fibroblastic anti-tumor activity in the pancreatic microenvironment.

Download Full-text

CXCR2-Dependent Accumulation of Tumor-Associated Neutrophils Regulates T-cell Immunity in Pancreatic Ductal Adenocarcinoma

Cancer Immunology Research ◽

10.1158/2326-6066.cir-16-0188 ◽

2016 ◽

Vol 4 (11) ◽

pp. 968-982 ◽

Cited By ~ 72

Author(s):

Timothy Chao ◽

Emma E. Furth ◽

Robert H. Vonderheide

Keyword(s):

T Cell ◽

Pancreatic Ductal Adenocarcinoma ◽

T Cell Immunity ◽

Ductal Adenocarcinoma ◽

Cell Immunity ◽

Tumor Associated Neutrophils

Download Full-text

Abstract IA38: Engineered T cell-receptor based therapy of pancreatic ductal adenocarcinoma

10.1158/2326-6074.cricimteatiaacr15-ia38 ◽

2016 ◽

Author(s):

Ingunn M. Stromnes ◽

Thomas M. Schmitt ◽

Scott J. Brockenbrough ◽

Hieu Nguyen ◽

Carlos Cuevas ◽

...

Keyword(s):

T Cell ◽

Pancreatic Ductal Adenocarcinoma ◽

T Cell Receptor ◽

Cell Receptor ◽

Ductal Adenocarcinoma

Download Full-text

Analysis of associations of CXCR3 ligands with immune microenvironment and aggressiveness in murine and human pancreatic ductal adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.762 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 762-762

Author(s):

Andrew Cannon ◽

Christopher M Thompson ◽

Pranita Atri ◽

Rakesh Bhatia ◽

Sushil Kumar ◽

...

Keyword(s):

Overall Survival ◽

T Cell ◽

Pancreatic Ductal Adenocarcinoma ◽

Nk Cell ◽

Cd8 T Cell ◽

High Expression ◽

Ductal Adenocarcinoma ◽

Bioinformatics Analyses ◽

Dismal Prognosis ◽

M1 Macrophage

762 Background: The complex milieu of cytokines within pancreatic ductal adenocarcinoma (PDAC) promotes tumor progression and immune suppression thereby contributing to the dismal prognosis of patients with PDAC. However, the roles of many cytokines, including CXCR3 ligands, in PDAC have not been thoroughly investigated. Methods: Bioinformatics analyses of PDAC microarray and TCGA datasets were used to identify cytokines overexpressed in PDAC, their association with patient survival as well as the expression of cognate cytokine receptors. Comparative analysis of cytokine expression in KrasLSL-G12D-P53LSL-R172H-Pdx1-Cre (KPC) and KrasLSL-G12D-Pdx1-Cre (KC) murine PDAC models were used to validate these findings. Pathway and CIBERSORT analyses were employed to determine mechanistic basis of altered survival associated with cytokines of interest. Results: Of the 149 cytokines analyzed, CXCR3 ligands CXCL9 and CXCL10 were highly and consistently overexpressed in PDAC datasets. Concurrently, CXCL9, CXCL10 and PF4 were overexpressed in the aggressive KPC murine model compared to the indolent KC model. CXCR3 showed robust expression in PDAC in microarray, TCGA and IHC analyses. Interestingly, high expression of CXCR3 ligands was associated with shorter overall survival (p = 0.04 for CXCL9, 10 and 11 and p = 0.02 for PF4) while high expression of CXCR3 was associated with increased overall survival (p = 0.03). Pathway analysis of genes correlated with CXCR3 and/or its ligands showed that CXCR3 ligands may promote T-cell exhaustion (p < 0.001). Finally, CIBERSORT analysis of TCGA data demonstrated that high CXCR3 expression was associated with increased CD8 T-cell and naïve B-cell signatures and loss of plasma cells signatures. High CXCR3 ligand expression was associated with increased CD8 T-cell, and M1 macrophage, and loss of NK-cell signatures(p < 0.05). Conclusions: CXCR3 ligands are overexpressed in PDAC and are associated with poor survival, likely related to alterations in tumor immune infiltrate/activity and may represent targets to augment anti-tumor immunity.

Download Full-text