Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency features

Valentin Picant, Lara Revol-Bauz, Laurie Tonon, Timothée Casini, Aurélien Voissière, Dominique Poujol, Emilie Picard, Céline Rodriguez, Cyril Degletagne, Emily Sible, Uzma Hasan, Anthony Ferrari, Christophe Caux and Nathalie Bendriss-Vermare ()
Additional contact information
Valentin Picant: Centre Léon Bérard
Lara Revol-Bauz: Centre Léon Bérard
Laurie Tonon: Centre Léon Bérard
Timothée Casini: Centre Léon Bérard
Aurélien Voissière: Centre Léon Bérard
Dominique Poujol: Centre Léon Bérard
Emilie Picard: Centre Léon Bérard
Céline Rodriguez: Centre Léon Bérard
Cyril Degletagne: Centre Léon Bérard
Emily Sible: INSERM U1111
Uzma Hasan: Centre Léon Bérard
Anthony Ferrari: Centre Léon Bérard
Christophe Caux: Centre Léon Bérard
Nathalie Bendriss-Vermare: Centre Léon Bérard

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Natural Killer (NK) cells play pivotal immunological roles including direct cytotoxic effector function and secretion of inflammatory and immunomodulating cytokines. In the context of chronic inflammation, NK cell fitness decreases during disease progression through currently unknown mechanisms. Here, we demonstrate that Interleukin-35 (IL-35) inhibits human NK cell proliferation, pro-inflammatory, and cytotoxic functions, while promoting secretion of TGF-β and proangiogenic factors in vitro. We show prolonged exposure to IL-35 converts both conventional and adaptive NK cells into CD9+CD103+CD49a+ ILC1-like cells via autocrine TGF-β. We assess cancer patient-derived public datasets and reveal the presence of IL-35-producing cells and IL-35-receptor-expressing NK/ILC1-like cells within the tumor microenvironment and associate IL-35 with poor prognosis. Collectively, our findings identify and implicate IL-35 as a key driver of NK cell plasticity, promoting the acquisition of features associated with tissue residency and weakened effector functions, and could be relevant in pathophysiological contexts, highlighting IL-35 as an attractive target for future immunotherapies aimed at enhancing NK cell clinical activity.

Date: 2025
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DOI: 10.1038/s41467-025-61196-0

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