An intestinal TH17 cell-derived subset can initiate cancer

Olivier Fesneau; Valentin Thevin; Valérie Pinet; Chloe Goldsmith; Baptiste Vieille; Saïdi M'Homa Soudja; Rossano Lattanzio; Michael Hahne; Valérie Dardalhon; Hector Hernandez-Vargas; Nicolas Benech; Julien C Marie

doi:10.1038/s41590-024-01909-7

An intestinal T_H17 cell-derived subset can initiate cancer

Nat Immunol. 2024 Sep;25(9):1637-1649. doi: 10.1038/s41590-024-01909-7. Epub 2024 Jul 26.

Authors

Affiliations

¹ Cancer Research Center of Lyon (CRCL) INSERM U 1052, CNRS UMR 5286, Centre Léon Bérard, Claude Bernard Lyon 1 University, Lyon, France.
² Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier, CNRS, Montpellier, France.
³ Department of Innovative Technologies in Medicine & Dentistry, Center for Advanced Studies and Technology (CAST), G. d'Annunzio University of Chieti-Pescara, Chieti, Italy.
⁴ Hospices Civils de Lyon, Service d'Hépato-Gastroentérologie, Croix Rousse Hospital, Lyon, France.
⁵ Cancer Research Center of Lyon (CRCL) INSERM U 1052, CNRS UMR 5286, Centre Léon Bérard, Claude Bernard Lyon 1 University, Lyon, France. [email protected].
⁶ Equipe Labellisée Ligue Nationale Contre le Cancer, Lyon, France. [email protected].

^# Contributed equally.

Abstract

Approximately 25% of cancers are preceded by chronic inflammation that occurs at the site of tumor development. However, whether this multifactorial oncogenic process, which commonly occurs in the intestines, can be initiated by a specific immune cell population is unclear. Here, we show that an intestinal T cell subset, derived from interleukin-17 (IL-17)-producing helper T (T_H17) cells, induces the spontaneous transformation of the intestinal epithelium. This subset produces inflammatory cytokines, and its tumorigenic potential is not dependent on IL-17 production but on the transcription factors KLF6 and T-BET and interferon-γ. The development of this cell type is inhibited by transforming growth factor-β1 (TGFβ1) produced by intestinal epithelial cells. TGFβ signaling acts on the pretumorigenic T_H17 cell subset, preventing its progression to the tumorigenic stage by inhibiting KLF6-dependent T-BET expression. This study therefore identifies an intestinal T cell subset initiating cancer.

MeSH terms

Animals
Cell Transformation, Neoplastic / immunology
Cell Transformation, Neoplastic / metabolism
Humans
Interferon-gamma / immunology
Interferon-gamma / metabolism
Interleukin-17 / immunology
Interleukin-17 / metabolism
Intestinal Mucosa* / immunology
Intestinal Mucosa* / metabolism
Intestinal Mucosa* / pathology
Intestinal Neoplasms / immunology
Intestinal Neoplasms / metabolism
Intestinal Neoplasms / pathology
Kruppel-Like Factor 6* / metabolism
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Proto-Oncogene Proteins / metabolism
Signal Transduction / immunology
T-Box Domain Proteins* / genetics
T-Box Domain Proteins* / metabolism
T-Lymphocyte Subsets / immunology
T-Lymphocyte Subsets / metabolism
Th17 Cells* / immunology
Transforming Growth Factor beta1 / metabolism

Substances

T-box transcription factor TBX21
T-Box Domain Proteins
Kruppel-Like Factor 6
Klf6 protein, mouse
Transforming Growth Factor beta1
Kruppel-Like Transcription Factors
Interferon-gamma
Interleukin-17
Proto-Oncogene Proteins