Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs

Eschweiler, Simon, Ramirez-Suastegui, Ciro, Li, Yingcong, King, Emma, Chudley, Lindsey, Thomas, Jaya, Wood, Oliver, von Witzleben, Adrian, Jeffrey, Danielle, McCann, Katy
et al (show 32 more authors) (2022) Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs. NATURE, 605 (7911). 741-+.

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Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies<sup>1-3</sup>. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity<sup>4,5</sup>, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (T<sub>reg</sub>) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on T<sub>reg</sub> cells. Accordingly, in mouse models, PI3Kδi decreased the number of T<sub>reg</sub> cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 T<sub>reg</sub> cells, accompanied by expansion of pathogenic T helper 17 (T<sub>H</sub>17) and type 17 CD8<sup>+</sup> T (T<sub>C</sub>17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.

Item Type: Article
Uncontrolled Keywords: Animals, Humans, Mice, Head and Neck Neoplasms, Disease Models, Animal, Quinolines, Adenosine, Antineoplastic Agents, Immunotherapy, T-Lymphocytes, Regulatory, Phosphatidylinositol 3-Kinases
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 18 Oct 2022 14:02
Last Modified: 18 Oct 2023 06:55
DOI: 10.1038/s41586-022-04685-2
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