PPARɣ drives IL-33-dependent ILC2 pro-tumoral functions

Giuseppe Ercolano, Alejandra Gomez-Cadena, Nina Dumauthioz, Giulia Vanoni, Mario Kreutzfeldt, Tania Wyss, Liliane Michalik, Romain Loyon, Angela Ianaro, Ping-Chih Ho, Christophe Borg, Manfred Kopf, Doron Merkler, Philippe Krebs, Pedro Romero, Sara Trabanelli and Camilla Jandus ()
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Giuseppe Ercolano: University of Geneva
Alejandra Gomez-Cadena: University of Geneva
Nina Dumauthioz: University of Lausanne
Giulia Vanoni: University of Lausanne
Mario Kreutzfeldt: University and University Hospitals of Geneva
Tania Wyss: University of Lausanne
Liliane Michalik: University of Lausanne
Romain Loyon: Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique
Angela Ianaro: University of Naples Federico II
Ping-Chih Ho: University of Lausanne
Christophe Borg: Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique
Manfred Kopf: ETH Zürich
Doron Merkler: University and University Hospitals of Geneva
Philippe Krebs: University of Bern
Pedro Romero: University of Lausanne
Sara Trabanelli: University of Geneva
Camilla Jandus: University of Geneva

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Group 2 innate lymphoid cells (ILC2s) play a critical role in protection against helminths and in diverse inflammatory diseases by responding to soluble factors such as the alarmin IL-33, that is often overexpressed in cancer. Nonetheless, regulatory factors that dictate ILC2 functions remain poorly studied. Here, we show that peroxisome proliferator-activated receptor gamma (PPARγ) is selectively expressed in ILC2s in humans and in mice, acting as a central functional regulator. Pharmacologic inhibition or genetic deletion of PPARγ in ILC2s significantly impair IL-33-induced Type-2 cytokine production and mitochondrial fitness. Further, PPARγ blockade in ILC2s disrupts their pro-tumoral effect induced by IL-33-secreting cancer cells. Lastly, genetic ablation of PPARγ in ILC2s significantly suppresses tumor growth in vivo. Our findings highlight a crucial role for PPARγ in supporting the IL-33 dependent pro-tumorigenic role of ILC2s and suggest that PPARγ can be considered as a druggable pathway in ILC2s to inhibit their effector functions. Hence, PPARγ targeting might be exploited in cancer immunotherapy and in other ILC2-driven mediated disorders, such as asthma and allergy.

Date: 2021
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DOI: 10.1038/s41467-021-22764-2

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