Activated Pancreatic Stellate Cells Sequester CD8+ T Cells to Reduce Their Infiltration of the Juxtatumoral Compartment of Pancreatic Ductal Adenocarcinoma

Abstract

Background & Aims Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic microenvironment that contains many different immune cells. Activated pancreatic stellate cells (PSCs) contribute to the desmoplasia. We investigated whether distinct stromal compartments are differentially infiltrated by different types of immune cells. Method We used tissue microarray analysis to compare immune cell infiltration of different pancreatico-biliary diseased tissues (PDAC, ampullary carcinoma, cholangiocarcinoma, mucinous cystic neoplasm, chronic inflammation, and chronic pancreatitis), and juxtatumoral stromal (<100 μm from tumor) and panstromal compartments. We investigated the association between immune infiltrate and patient survival times. We analyzed T-cell migration and tumor infiltration in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice, and the effects of all-trans retinoic acid (ATRA) on these processes. Results Juxtatumoral compartments in PDAC samples from 2 independent groups of patients contained increased numbers of myeloperoxidase+ and CD68+ cells, compared with panstromal compartments. However, juxtatumoral compartments of PDACs contained fewer CD8+, FoxP3+, CD56+, or CD20+ cells than panstromal compartments, a distinction absent in ampullary carcinomas and cholangiocarcinomas. Patients with PDACs that had high densities of CD8+ T-cells in the juxtatumoral compartment had longer survival times than patients with lower densities. In KPC mice, administration of ATRA, which renders PSCs quiescent, increased numbers of CD8+ T-cells in juxtatumoral compartments. We found that activated PSCs express cytokines, chemokines, and adhesion molecules that regulate T-cell migration. In vitro migration assays showed that CD8+ T-cells from PDAC patients had increased chemotaxis towards activated PSCs, which secrete CXCL12, compared with quiescent PSC or tumor cells. These effects could be reversed by knockdown of CXCL12 or treatment of PSCs with ATRA. Conclusion Based on studies of human PDAC samples and KPC mice, activated PSCs appear to reduce migration of CD8+ T-cells to juxtatumoral stromal compartments, preventing their access to cancer cells. Deregulated signaling by activated PSCs could prevent an effective anti-tumor immune response.

Inflammation and pancreatic cancer: disease promoter and new therapeutic target

“…T-cell infiltrate around cancer cells was correlated with improved survival after surgery, suggesting this immune reaction against cancer cells directly affects the clinical outcome [89]. This study clarified the detailed mechanism of immunosuppression by PSCs using a KPC mouse model.…”

Scientific rationale for integrative and personalised strategies for pancreatic ductal adenocarcinoma management

“…PSCs have an important role in mediating the immunosuppressive microenvironment in PDAC by promoting proliferation and activation of MDSCs via secreting cytokines and VEGF, impairing the survival of T cells, recruiting Treg and sequestering CTLs via CXCL12/CXCR2, and CXCL12/CXCR4, respectively, impeding their contact with tumour cells [107][108][109]. Therefore, T-lymphocytes were shown to surround the pancreatic lesions and found more frequently in the fibrotic interstitial tissue than in the intraepithelial area of the PDAC [109].…”

“…Therefore, T-lymphocytes were shown to surround the pancreatic lesions and found more frequently in the fibrotic interstitial tissue than in the intraepithelial area of the PDAC [109]. PSCs release IL-33 to activate mast cells to produce pro-inflammatory cytokine, MMPs production promoting PDAC progression [91].…”

Desmoplastic Reaction In Pancreatic Ductal Adenocarcinoma

“…40,41 Higher levels of CD8 positive T-cell infiltration have been shown to correlate with a better survival, 40,41 while macrophage and neutrophil infiltration as well as high levels of MDSCs have been reported to be associated with poor survival. 40 The infiltration of MDSCs in PDAC tissue leads to the establishment of antigen-specific T-cell tolerance, which might enable cancer cells to escape from immune surveillance.…”

“…44 It has been reported that PSCs negatively modulate immune responses via reducing the migration of CD8 positive T-cells to cancer cells in human PDAC and the KPC mouse model of pancreatic cancer. 41 Additionally, PSCs have been shown to activate mast cells in vitro promoting tryptase and IL13 release from the latter. These mast cell-derived factors have been shown to stimulate cancer cell proliferation.…”