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

Nat Commun. 2021 May 5;12(1):2538. doi: 10.1038/s41467-021-22764-2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma
  • Cytokines / pharmacology
  • Gene Knockdown Techniques
  • Humans
  • Hypersensitivity
  • Immunity, Innate / immunology*
  • Immunotherapy
  • Interleukin-33 / metabolism*
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*

Substances

  • Cytokines
  • Il33 protein, mouse
  • Interleukin-33
  • PPAR gamma