Loading...
Intermittent PI3Ko inhibition sustains anti-tumor immunity and curbs irAEs
Eschweiler, S. Ramirez-Suastegui, C. Li, Y. King, E. Chudley, L. Thomas, J. Wood, O. von Witzleben, A. Jeffrey, D. McCann, K.
Eschweiler, S.
Ramirez-Suastegui, C.
Li, Y.
King, E.
Chudley, L.
Thomas, J.
Wood, O.
von Witzleben, A.
Jeffrey, D.
McCann, K.
Publication Date
2022-05-26
End of Embargo
Supervisor
Rights
(c) 2022 The Authors. This is an Open Access article distributed under the Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/)
Peer-Reviewed
Yes
Open Access status
openAccess
Accepted for publication
2022-03-24
Institution
Department
Awarded
Embargo end date
Collections
Additional title
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.
Version
Published version
Citation
Eschweiler S, Ramírez-Suástegui C, Li Y et al (2022) Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs. Nature. 605: 741-746.
Link to publisher’s version
Link to published version
Link to Version of Record
Type
Article
Qualification name
Notes
Research Development Fund Publication Prize Award winner, May 2022.