1. Single-cell RNA-sequencing of human spleens reveals an IDO-1 + tolerogenic dendritic cell subset in pancreatic cancer patients that is absent in normal individuals.
- Author
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Mundry CS, Triplett AA, Shah OS, Chaitankar V, McAndrews KL, Ly QP, Cox JL, Eberle KC, Mehla K, Swanson BJ, Lazenby A, Klute KA, Grandgenett PM, and Hollingsworth MA
- Subjects
- Humans, Immune Tolerance, Carcinoma, Pancreatic Ductal immunology, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Sequence Analysis, RNA methods, Tumor Microenvironment immunology, RNA-Seq, Dendritic Cells immunology, Indoleamine-Pyrrole 2,3,-Dioxygenase genetics, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Pancreatic Neoplasms immunology, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Spleen immunology, Single-Cell Analysis methods
- Abstract
Local and systemic immunosuppression are prominent features of pancreatic cancer, rendering anti-tumor effector cells inactive and immunotherapeutic approaches ineffective. The spleen, an understudied point of antigen-presentation and T cell priming in humans, holds particular importance in pancreatic cancer due to its proximity to the developing tumor. As main effectors of antigen presentation, dendritic cells display antigens to lymphocytes, thereby bridging the innate and adaptive immune response. While tumor-infiltrating anti-inflammatory dendritic cells have been described, splenic dendritic cells have historically just been considered to stimulate the anti-tumor immune response. Here, we describe, for the first time, the presence of an immunosuppressive, tolerogenic IDO1
+ dendritic cell subset in the spleens of pancreatic cancer patients that likely contributes to systemic immunosuppression that is associated with pancreatic ductal adenocarcinoma. Network analysis of scRNA seq data reveals extensive communication networks between the identified tolerogenic DC cluster and numerous immune cell populations in the spleen. Interactions with innate and adaptive immune cells suggest a broad influence on leukocyte trafficking and immune regulation within the spleen microenvironment. The identification of signaling pathways involving AHR and IDO-1, CCL19, NECTIN2, CLEC2D, and others elucidates potential mechanisms underlying the immunosuppressive functions of this cell type., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.) more...- Published
- 2024
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