Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs

Collapse authors list.
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: 0000-0001-7027-8997, 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 ORCID: 0000-0002-4058-6013, Ay, Ferhat, Friberg, Greg, Kronenberg, Mitchell, Vanhaesebroeck, Bart, Vijayanand, Pandurangan and Ottensmeier, Christian H ORCID: 0000-0003-3619-1657 (2022) Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs. NATURE, 605 (7911). 741-+. ISSN 0028-0836, 1476-4687

Access the full-text of this item by clicking on the Open Access link.

Text Intermittent PI3K - Published version Download (0B)

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:	06 Dec 2024 20:08
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