Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma

Gastroenterology. 2013 Nov;145(5):1121-32. doi: 10.1053/j.gastro.2013.07.025. Epub 2013 Jul 25.


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.

Methods: We used tissue microarray analysis to compare immune cell infiltration of different pancreaticobiliary 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 also 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 patients with PDAC, had increased chemotaxis toward activated PSCs, which secrete CXCL12, compared with quiescent PSCs or tumor cells. These effects could be reversed by knockdown of CXCL12 or treatment of PSCs with ATRA.

Conclusions: 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 antitumor immune response.

Keywords: AC; ATRA; Antitumor Immunity; CC; Immune Regulation; MDSC; Mouse Model; PBD; PDAC; PSC; Pancreatic Cancer; TMA; Treg; aPSC; activated pancreatic stellate cell; all-trans retinoic acid; ampullary carcinoma; cholangiocarcinoma; myeloid-derived suppressor cell; pancreatic ductal adenocarcinoma; pancreatic stellate cell; pancreaticobiliary disease; qPSC; quiescent pancreatic stellate cell; regulatory T cell; tissue microarray.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology*
  • Adenocarcinoma / physiopathology
  • Animals
  • Antigens, CD20 / physiology
  • CD56 Antigen / physiology
  • CD8-Positive T-Lymphocytes / pathology*
  • Carcinoma, Pancreatic Ductal / pathology*
  • Carcinoma, Pancreatic Ductal / physiopathology
  • Cell Adhesion / physiology
  • Cell Movement / physiology*
  • Cells, Cultured
  • Chemokine CXCL12 / physiology
  • Disease Models, Animal
  • Forkhead Transcription Factors / physiology
  • Humans
  • Mice
  • Mice, Inbred Strains
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Neoplasms / physiopathology
  • Pancreatic Stellate Cells / pathology*


  • Antigens, CD20
  • CD56 Antigen
  • Chemokine CXCL12
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • NCAM1 protein, human