Intermittent PI3K delta inhibition sustains anti-tumour immunity and curbs irAEs

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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) , Simon, Hayley, Mondal, Monalisa, Wang, Alice, Dicker, Martina, Lopez-Guadamillas, Elena, Chou, Ting-Fang, Dobbs, Nicola A, Essame, Louisa, Acton, Gary, Kelly, Fiona, Halbert, Gavin, Sacco, Joseph J, Schache, Andrew Graeme ORCID: 0000-0001-9466-6038, Shaw, Richard ORCID: 0000-0002-5157-4042, McCaul, James Anthony, Paterson, Claire, Davies, Joseph H, Brennan, Peter A, Singh, Rabindra P, Loadman, Paul M, Wilson, William, Hackshaw, Allan, Seumois, Gregory, Okkenhaug, Klaus, Thomas, Gareth J, Jones, Terry M, Ay, Ferhat, Friberg, Greg, Kronenberg, Mitchell, Vanhaesebroeck, Bart, Vijayanand, Pandurangan and Ottensmeier, Christian H ORCID: 0000-0003-3619-1657 (2022) Intermittent PI3K delta inhibition sustains anti-tumour immunity and curbs irAEs. NATURE, 605 (7911). 741-+.

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Abstract

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^1-3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity^4,5, 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_reg) 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_reg cells. Accordingly, in mouse models, PI3Kδi decreased the number of T_reg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 T_reg cells, accompanied by expansion of pathogenic T helper 17 (T_H17) and type 17 CD8⁺ T (T_C17) 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 Jan 2023 19:49
DOI:	10.1038/s41586-022-04685-2
Open Access URL:	https://www.nature.com/articles/s41586-022-04685-2
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3165609