Interleukins 15 and 18 synergistically prime the antitumor function of natural killer cells through noncanonical activation of mTORC1
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.
Authors
- Sarah Benezech (ORCID: https://orcid.org/0000-0002-9587-3896)
- Anaïs Nombel (ORCID: https://orcid.org/0009-0007-8564-9034)
- Noëmi Rousseaux (ORCID: https://orcid.org/0000-0002-7152-1300)
- Romain Roncagalli (ORCID: https://orcid.org/0000-0001-7554-0552)
- Anne Gonzalez de Peredo (ORCID: https://orcid.org/0000-0001-6152-6311)
- Emilie Bourdonnay (ORCID: https://orcid.org/0000-0002-3579-5478)
- Lucie Fallone (ORCID: https://orcid.org/0009-0005-6863-3140)
- Annabelle Drouillard (ORCID: https://orcid.org/0000-0001-7188-7655)
- Kévin Pouxvielh (ORCID: https://orcid.org/0009-0001-4785-9272)
- Anne‐Laure Mathieu (ORCID: https://orcid.org/0000-0002-2893-7001)
- Erwan Mortier (ORCID: https://orcid.org/0000-0002-6321-6488)
- Antoine Marçais (ORCID: https://orcid.org/0000-0002-3591-6268)
- Thierry Walzer (ORCID: https://orcid.org/0000-0002-0857-8179)
- Sophie Degouve
- Karima Chaoui (ORCID: https://orcid.org/0009-0001-4861-0102)
- Louis Picq
- Pierre Machy (ORCID: https://orcid.org/0009-0003-9728-2576)
- Eléonore Bouscasse
- Laure Arbez
Institutions
- Université Claude Bernard Lyon 1 (FR)
- École Normale Supérieure de Lyon (FR)
- Centre National de la Recherche Scientifique (FR)
- Université Toulouse III - Paul Sabatier (FR)
- Inserm (FR)
- Aix-Marseille Université (FR)
- Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers (FR)
- Institut de Pharmacologie et de Biologie Structurale (FR)
- Laboratoire Vision Action Cognition (FR)
- Centre d’Immunologie de Marseille-Luminy (FR)
- Centre International de Recherche en Infectiologie (FR)
- Nantes Université (FR)
Publication Details
- Journal
- Science Signaling
- Published
- 2025-09-16
- DOI
- https://doi.org/10.1126/scisignal.adq8778
- Citations
- 1
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.80