 Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEsSimon Eschweiler,
Ciro Ramírez-Suástegui,
Yingcong Li,
Emma King,
Lindsey Chudley,
Jaya Thomas,
Oliver Wood,
Adrian Witzleben,
Danielle Jeffrey,
Katy McCann,
Hayley Simon,
Monalisa Mondal,
Alice Wang,
Martina Dicker,
Elena Lopez-Guadamillas,
Ting-Fang Chou,
Nicola A. Dobbs,
Louisa Essame,
Gary Acton,
Fiona Kelly,
Gavin Halbert,
Joseph J. Sacco,
Andrew Graeme Schache,
Richard Shaw,
James Anthony McCaul,
Claire Paterson,
Joseph H. Davies,
Peter A. Brennan,
Rabindra P. Singh,
Paul M. Loadman,
William Wilson,
Allan Hackshaw,
Gregory Seumois,
Klaus Okkenhaug,
Gareth J. Thomas,
Terry M. Jones,
Ferhat Ay,
Greg Friberg,
Mitchell Kronenberg,
Bart Vanhaesebroeck,
Pandurangan Vijayanand () and
Christian H. Ottensmeier ()
Nature, 2022, vol. 605, issue 7911, 741-746 Abstract: 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 malignancies1–3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, 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 (Treg) 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 Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) 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. Date: 2022 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:605:y:2022:i:7911:d:10.1038_s41586-022-04685-2 Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-022-04685-2 Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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