Inositol phosphatase INPP4B sustains ILC1s and intratumoral NK cells through an AKT-driven pathway.

Vincent Peng, Tihana Trsan, Raki Sudan, Bishan Bhattarai, Victor S Cortez, Martina Molgora, Jean Vacher, Marco Colonna

The Journal of experimental medicine 2024 Mar 04

filter terms:

Innate lymphoid cells (ILCs) are a heterogeneous population of lymphocytes that coordinate early immune responses and maintain tissue homeostasis. Type 1 innate immune responses are mediated by natural killer (NK) cells and group 1 ILCs (ILC1s). Despite their shared features, NK cells and ILC1s display profound differences among various tissue microenvironments. Here, we identify the inositol polyphosphatase INPP4B as a hallmark feature of tissue-resident ILC1s and intratumoral NK cells using an scRNA-seq atlas of tissue-associated and circulating NK/ILC1s. Conditional deletion of Inpp4b in ILC1s and NK cells reveals that it is necessary for the homeostasis of tissue-resident ILC1s but not circulating NK cells at steady-state. Inpp4b-deficient cells display increased rates of apoptosis and reduced activation of the prosurvival molecule AKT. Furthermore, expression of Inpp4b by NK/ILC1s is necessary for their presence in the intratumoral environment, and lack of Inpp4b impairs antitumor immunity. These findings highlight INPP4B as a novel regulator of tissue residency and antitumor function in ILC1s and NK cells. © 2024 Crown copyright. The government of Australia, Canada, or the UK ("the Crown") owns the copyright interests of authors who are government employees. The Crown Copyright is not transferable.

Citation

Vincent Peng, Tihana Trsan, Raki Sudan, Bishan Bhattarai, Victor S Cortez, Martina Molgora, Jean Vacher, Marco Colonna. Inositol phosphatase INPP4B sustains ILC1s and intratumoral NK cells through an AKT-driven pathway. The Journal of experimental medicine. 2024 Mar 04;221(3)