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 Köpf, Doron Merkler, Philippe Krebs, Pedro Romero, Sara Trabanelli, Camilla Jandus
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.