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

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

doi:10.1038/s41590-024-01755-7

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

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 KöhlerRobert Zeiser, Mohamed Oukka, Thomas Korn, Sonia Tugues, Burkhard Becher

Publikation: Beitrag in Fachzeitschrift › Artikel › Begutachtung

1 Zitat (Scopus)

Abstract

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 (T_reg) 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 T_reg 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 T_reg 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.

Originalsprache	Englisch
Seiten (von - bis)	512-524
Seitenumfang	13
Fachzeitschrift	Nature Immunology
Jahrgang	25
Ausgabenummer	3
DOIs	https://doi.org/10.1038/s41590-024-01755-7
Publikationsstatus	Veröffentlicht - März 2024
Extern publiziert	Ja

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Wertheimer, T., Zwicky, P., Rindlisbacher, L., Sparano, C., Vermeer, M., de Melo, B. M. S., Haftmann, C., Rückert, T., Sethi, A., Schärli, S., Huber, A., Ingelfinger, F., Xu, C., Kim, D., Häne, P., Fonseca da Silva, A., Muschaweckh, A., Nunez, N., Krishnarajah, S., ... Becher, B. (2024). IL-23 stabilizes an effector T_reg cell program in the tumor microenvironment. Nature Immunology, 25(3), 512-524. https://doi.org/10.1038/s41590-024-01755-7

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title = "IL-23 stabilizes an effector Treg cell program in the tumor microenvironment",

abstract = "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.",

author = "Tobias Wertheimer and Pascale Zwicky and Lukas Rindlisbacher and Colin Sparano and Marijne Vermeer and {de Melo}, {Bruno Marcel Silva} and Claudia Haftmann and Tamina R{\"u}ckert and Aakriti Sethi and Stefanie Sch{\"a}rli and Anna Huber and Florian Ingelfinger and Caroline Xu and Daehong Kim and Philipp H{\"a}ne and {Fonseca da Silva}, Andr{\'e} and Andreas Muschaweckh and Nicolas Nunez and Sinduya Krishnarajah and Natalie K{\"o}hler and Robert Zeiser and Mohamed Oukka and Thomas Korn and Sonia Tugues and Burkhard Becher",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = mar,

doi = "10.1038/s41590-024-01755-7",

language = "English",

volume = "25",

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Wertheimer, T, Zwicky, P, Rindlisbacher, L, Sparano, C, Vermeer, M, de Melo, BMS, Haftmann, C, Rückert, T, Sethi, A, Schärli, S, Huber, A, Ingelfinger, F, Xu, C, Kim, D, Häne, P, Fonseca da Silva, A, Muschaweckh, A, Nunez, N, Krishnarajah, S, Köhler, N, Zeiser, R, Oukka, M, Korn, T, Tugues, S & Becher, B 2024, 'IL-23 stabilizes an effector T_reg cell program in the tumor microenvironment', Nature Immunology, Jg. 25, Nr. 3, S. 512-524. https://doi.org/10.1038/s41590-024-01755-7

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T1 - IL-23 stabilizes an effector Treg cell program in the tumor microenvironment

AU - Wertheimer, Tobias

AU - Zwicky, Pascale

AU - Rindlisbacher, Lukas

AU - Sparano, Colin

AU - Vermeer, Marijne

AU - de Melo, Bruno Marcel Silva

AU - Haftmann, Claudia

AU - Rückert, Tamina

AU - Sethi, Aakriti

AU - Schärli, Stefanie

AU - Huber, Anna

AU - Ingelfinger, Florian

AU - Xu, Caroline

AU - Kim, Daehong

AU - Häne, Philipp

AU - Fonseca da Silva, André

AU - Muschaweckh, Andreas

AU - Nunez, Nicolas

AU - Krishnarajah, Sinduya

AU - Köhler, Natalie

AU - Zeiser, Robert

AU - Oukka, Mohamed

AU - Korn, Thomas

AU - Tugues, Sonia

AU - Becher, Burkhard

PY - 2024/3

Y1 - 2024/3

N2 - 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.

AB - 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.

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U2 - 10.1038/s41590-024-01755-7

DO - 10.1038/s41590-024-01755-7

M3 - Article

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SN - 1529-2908

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EP - 524

JO - Nature Immunology

JF - Nature Immunology

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