Tumor-associated macrophages promote intratumoral conversion of conventional CD4+ T cells into regulatory T cells via PD-1 signalling
Kos, Kevin; Salvagno, Camilla; Wellenstein, Max D.; Aslam, Muhammad A.; Meijer, Denize A.; Hau, Cheei Sing; Vrijland, Kim; Kaldenbach, Daphne; Raeven, Elisabeth A.M.; Schmittnaegel, Martina; Ries, Carola H.; de Visser, Karin E.
(2022) OncoImmunology, volume 11, issue 1, pp. 1 - 15
(Article)
Abstract
While regulatory T cells (Tregs) and macrophages have been recognized as key orchestrators of cancer-associated immunosuppression, their cellular crosstalk within tumors has been poorly characterized. Here, using spontaneous models for breast cancer, we demonstrate that tumor-associated macrophages (TAMs) contribute to the intratumoral accumulation of Tregs by promoting the conversion of
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conventional CD4+ T cells (Tconvs) into Tregs. Mechanistically, two processes were identified that independently contribute to this process. While TAM-derived TGF-β directly promotes the conversion of CD4+ Tconvs into Tregs in vitro, we additionally show that TAMs enhance PD-1 expression on CD4+ T cells. This indirectly contributes to the intratumoral accumulation of Tregs, as loss of PD-1 on CD4+ Tconvs abrogates intratumoral conversion of adoptively transferred CD4+ Tconvs into Tregs. Combined, this study provides insights into the complex immune cell crosstalk between CD4+ T cells and TAMs in the tumor microenvironment of breast cancer, and further highlights that therapeutic exploitation of macrophages may be an attractive immune intervention to limit the accumulation of Tregs in breast tumors.
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Keywords: Breast cancer immunology, regulatory T cells, T cell plasticity, tumor-associated macrophages, Humans, Immune Tolerance, T-Lymphocytes, Regulatory, Tumor Microenvironment, Tumor-Associated Macrophages, Female, Programmed Cell Death 1 Receptor, Breast Neoplasms, Oncology, Immunology and Allergy, Immunology, Journal Article
ISSN: 2162-4011
Publisher: Landes Bioscience
Note: Funding Information: This work was supported by the European Research Council [615300]; Dutch Cancer Society [10083, 10623, 13191]; Nederlandse organisatie voor wetenschappelijk onderzoek (NWO) [91819616] and Oncode Institute. K.K. is funded by the NWO Oncology Graduate School Amsterdam (OOA) Diamond Program We acknowledge members of the Tumor Biology & Immunology Department, NKI for their insightful input. We thank the flow cytometry facility, genomics core facility, animal laboratory facility, transgenesis facility, and animal pathology facility of the Netherlands Cancer Institute for technical assistance. Components of the graphical abstract were prepared using Servier Medical Art, licensed under Creative Commons Attribution 3.0 Unported License. Publisher Copyright: © 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.
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