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Cited by 579Pancreatic and Hepatic Oncology ResearchPancreatitis Pathology and TreatmentCancer Immunotherapy and Biomarkers

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

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Ene–Obong, Abasi, Clear, Andrew J., Watt, Jennifer, Wang, Jun, Fatah, Rewas, Riches, John C., Marshall, John F., Chin–Aleong, Joanne +4 more·2013·Gastroenterology
DOI 10.1053/j.gastro.2013.07.025PMC PMC3896919
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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. 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.

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  • In pancreatic ductal adenocarcinoma, CAFs inhibit CD8+ T cell infiltration by secreting CXCL12.

    “in pancreatic ductal adenocarcinoma, CAFs inhibit CD8+ T cell infiltration by secreting CXCL12 73.”

    From TBX3 shapes an immunosuppressive microenvironment and induces immunotherapy resistance (2025) · cites this paper as [73]

    The Results section reports that activated pancreatic stellate cells secrete CXCL12 and that knocking it down reduces CD8+ T-cell migration toward those cells in vitro. The paper also reports fewer CD8+ T cells in the juxtatumoral compartment of PDAC, but it does not establish that CXCL12 secretion itself causes the reduced infiltration in vivo. The claim states that mechanism more definitively than the evidence supports. (LLM, conf=0.84)

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Authors
Ene–Obong, A., Clear, A. J., Watt, J., Wang, J., Fatah, R., Riches, J. C., Marshall, J. F., Chin–Aleong, J., Chelala, C., Gribben, J. G., Ramsay, A. G., & Kocher, H. M.
Affiliations
Queen Mary University of London (GB)
Corresponding author
Kocher, Hemant M.
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2013-11
Volume
145
Issue
5
Pages
1121-1132
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2013.07.025
PMC
PMC3896919
OpenAlex
W2071462987
Cited by
579
References
2
Citations by year
2026: 35 · 2025: 42 · 2024: 62 · 2023: 55 · 2022: 64 · 2021: 61 · 2020: 66 · 2019: 56 · 2018: 41 · 2017: 31 · 2016: 25 · 2015: 18 · 2014: 17 · 2013: 5
FWCI
11.79
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Research Portal (King's College London) (submittedVersion)
Funders
  • Cancer Research UK (12008)
  • National Institute for Health and Care Research
  • Barts Health NHS Trust
  • National Institutes of Health
  • National Cancer Institute (P20CA081534)
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
pancreatic ductal adenocarcinoma, pancreatic stellate cells, CD8+ T cells, tumor immune microenvironment, desmoplasia, T cell migration, CXCL12, all-trans retinoic acid, KPC mice, chemokines, chemotaxis, patient survival, ampullary carcinoma, cholangiocarcinoma
MeSH terms
Adenocarcinoma, Animals, Cell Adhesion, Cell Movement, Cells, Cultured, Disease Models, Animal, Humans, Mice, Inbred Strains, Pancreatic Neoplasms, CD8-Positive T-Lymphocytes, Antigens, CD20, CD56 Antigen, Carcinoma, Pancreatic Ductal, Mice, Forkhead Transcription Factors, Chemokine CXCL12, Pancreatic Stellate Cells

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