Dataset Information

Human Pancreatic Carcinoma-Associated Fibroblasts Promote Expression of Co-inhibitory Markers on CD4⁺ and CD8⁺ T-Cells.

ABSTRACT: Carcinoma-associated pancreatic fibroblasts (CAFs) are the major type of cells in the stroma of pancreatic ductal adenocarcinomas and besides their pathological release of extracellular matrix proteins, they are also perceived as key contributors to immune evasion. Despite the known relevance of tumor infiltrating lymphocytes in cancers, the interactions between T-cells and CAFs remain largely unexplored. Here, we found that CAFs isolated from tumors of pancreatic cancer patients undergoing surgical resection (n = 15) expressed higher levels of the PD-1 ligands PD-L1 and PD-L2 compared to primary skin fibroblasts from healthy donors. CAFs strongly inhibited T-cell proliferation in a contact-independent fashion. Blocking the activity of prostaglandin E₂ (PGE₂) by indomethacin partially restored the proliferative capacity of both CD4⁺ and CD8⁺ T-cells. After stimulation, the proportion of proliferating T-cells expressing HLA-DR and the proportion of memory T-cells were decreased when CAFs were present compared to T-cells proliferating in the absence of CAFs. Interestingly, CAFs promoted the expression of TIM-3, PD-1, CTLA-4 and LAG-3 in proliferating T-cells. Immunohistochemistry stainings further showed that T-cells residing within the desmoplastic stromal compartment express PD-1, indicating a role for CAFs on co-inhibitory marker expression also in vivo. We further found that PGE₂ promoted the expression of PD-1 and TIM-3 on T-cells. Functional assays showed that proliferating T-cells expressing immune checkpoints produced less IFN-?, TNF-?, and CD107a after restimulation when CAFs had been present. Thus, this indicates that CAFs induce expression of immune checkpoints on CD4⁺ and CD8⁺ T-cells, which contribute to a diminished immune function.

SUBMITTER: Gorchs L

PROVIDER: S-EPMC6491453 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Human Pancreatic Carcinoma-Associated Fibroblasts Promote Expression of Co-inhibitory Markers on CD4<sup>+</sup> and CD8<sup>+</sup> T-Cells.

Gorchs Laia L Fernández Moro Carlos C Bankhead Peter P Kern Katharina P KP Sadeak Imrul I Meng Qingda Q Rangelova Elena E Kaipe Helen H

Frontiers in immunology 20190424

Carcinoma-associated pancreatic fibroblasts (CAFs) are the major type of cells in the stroma of pancreatic ductal adenocarcinomas and besides their pathological release of extracellular matrix proteins, they are also perceived as key contributors to immune evasion. Despite the known relevance of tumor infiltrating lymphocytes in cancers, the interactions between T-cells and CAFs remain largely unexplored. Here, we found that CAFs isolated from tumors of pancreatic cancer patients undergoing surg ...[more]

PMID: 31068935

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Dataset Information

Human Pancreatic Carcinoma-Associated Fibroblasts Promote Expression of Co-inhibitory Markers on CD4⁺ and CD8⁺ T-Cells.

Publications

Human Pancreatic Carcinoma-Associated Fibroblasts Promote Expression of Co-inhibitory Markers on CD4<sup>+</sup> and CD8<sup>+</sup> T-Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Human Pancreatic Carcinoma-Associated Fibroblasts Promote Expression of Co-inhibitory Markers on CD4+ and CD8+ T-Cells.

Publications

Human Pancreatic Carcinoma-Associated Fibroblasts Promote Expression of Co-inhibitory Markers on CD4<sup>+</sup> and CD8<sup>+</sup> T-Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Human Pancreatic Carcinoma-Associated Fibroblasts Promote Expression of Co-inhibitory Markers on CD4⁺ and CD8⁺ T-Cells.