IL-23 stabilizes an effector Treg cell program in the tumor microenvironment.

Interleukin-23 (IL-23) is a proinflammatory cytokine mainly produced by myeloid cells that promotes tumor growth in various preclinical cancer models and correlates with adverse outcomes. However, as to how IL-23 fuels tumor growth is unclear. Here, we found tumor-associated macrophages to be the main source of IL-23 in mouse and human tumor microenvironments. Among IL-23-sensing cells, we identified a subset of tumor-infiltrating regulatory T (Treg) cells that display a highly suppressive phenotype across mouse and human tumors. The use of three preclinical models of solid cancer in combination with genetic ablation of Il23r in Treg cells revealed that they are responsible for the tumor-promoting effect of IL-23. Mechanistically, we found that IL-23 sensing represents a crucial signal driving the maintenance and stabilization of effector Treg cells involving the transcription factor Foxp3. Our data support that targeting the IL-23/IL-23R axis in cancer may represent a means of eliciting antitumor immunity. © 2024. The Author(s).

Citation

Tobias Wertheimer, Pascale Zwicky, Lukas Rindlisbacher, Colin Sparano, Marijne Vermeer, Bruno Marcel Silva de Melo, Claudia Haftmann, Tamina Rückert, Aakriti Sethi, Stefanie Schärli, Anna Huber, Florian Ingelfinger, Caroline Xu, Daehong Kim, Philipp Häne, André Fonseca da Silva, Andreas Muschaweckh, Nicolas Nunez, Sinduya Krishnarajah, Natalie Köhler, Robert Zeiser, Mohamed Oukka, Thomas Korn, Sonia Tugues, Burkhard Becher. IL-23 stabilizes an effector Treg cell program in the tumor microenvironment. Nature immunology. 2024 Mar;25(3):512-524

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PMID: 38356059

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