2. Academic Validation
  3. Interleukins 15 and 18 synergistically prime the antitumor function of natural killer cells through noncanonical activation of mTORC1

Interleukins 15 and 18 synergistically prime the antitumor function of natural killer cells through noncanonical activation of mTORC1

  • Sci Signal. 2025 Sep 16;18(904):eadq8778. doi: 10.1126/scisignal.adq8778.
Lucie Fallone 1,  Kévin Pouxvielh 1,  Laure Arbez 1,  Noëmi Rousseaux 1,  Louis Picq 1 2,  Annabelle Drouillard 1,  Anne-Laure Mathieu 1,  Anaïs Nombel 1,  Sarah Benezech 1,  Emilie Bourdonnay 3,  Sophie Degouve 1,  Pierre Machy 4,  Erwan Mortier 4,  Eléonore Bouscasse 5,  Karima Chaoui 5,  Bernard Malissen 6 7,  Anne Gonzalez de Peredo 5,  Romain Roncagalli 6,  Thierry Walzer 1,  Antoine Marçais 1
Affiliations

Affiliations

  • 1 CIRI, Centre International de Recherche en Infectiologie, (Team Lyacts), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France.
  • 2 Institut Roche, F-92100, Boulogne-Billancourt, France.
  • 3 CIRI, Centre International de Recherche en Infectiologie, (Team I2BA), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France.
  • 4 Nantes Université, CNRS, Inserm, CRCI2NA, F-44000, Nantes, France.
  • 5 Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UPS), F-31400, Toulouse, France.
  • 6 Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRS, F-13009, Marseille, France.
  • 7 CIPHE, Centre d'Immunophénomique, Aix Marseille Université, INSERM, CNRS UMR, F-13009, Marseille, France.
PMID: 40956875 DOI: 10.1126/scisignal.adq8778
Abstract

The multiprotein complex mTORC1 is essential for the increase in protein synthesis and bioenergetic metabolism that supports the proliferation of many cell types, including natural killer (NK) cells, which are important innate effectors of the antitumoral response. Here, we investigated the mechanisms of mTORC1 activation in NK cells by interleukin-15 (IL-15) and IL-18, which promote NK cell function and are components of a cytokine cocktail used to preactivate NK cells for Cancer Immunotherapy. Through genetic and pharmacological approaches, we showed that IL-15 activated mTORC1 through the PI3K/Akt/ERK pathway, whereas IL-18 signaled through the p38 effectors MK2 and MK3 in both murine and human primary NK cells. Both pathways synergized to promote NK cell proliferation and effector functions in an mTORC1-dependent manner. Moreover, both pathways operated independently of the inhibitor TSC and the activator Rheb, revealing a noncanonical mode of mTORC1 activation by cytokines. Treating mice with IL-15 and IL-18 in combination led to increased NK cell numbers and improved antitumoral activity, suggesting that this cytokine combination could be exploited to enhance NK cell potential in therapeutic settings.

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