Treg-driven tumour control by PI3Kδ inhibition limits myeloid-derived suppressor cell expansion

Lauder, Sarah N., Smart, Kathryn, Bart, Valentina M. T., Pires, Ana, Scott, Jake, Milutinovic, Stefan ORCID: https://orcid.org/0000-0002-3163-3383, Godkin, Andrew ORCID: https://orcid.org/0000-0002-1910-7567, Vanhaesebroeck, Bart and Gallimore, Awen ORCID: https://orcid.org/0000-0001-6675-7004 2022. Treg-driven tumour control by PI3Kδ inhibition limits myeloid-derived suppressor cell expansion. British Journal of Cancer 127 , 1595–1602. 10.1038/s41416-022-01917-0

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Abstract

Background Recent studies have demonstrated that blocking the PI3Kδ signalling enzyme (by administering a small molecule inhibitor, PI-3065) can potently improve the anti-tumour T-cell response through direct inhibition of Tregs. This treatment also has a negative impact on MDSC numbers but the primary mechanism driving this effect has remained unclear. Methods The 4T1 breast cancer mouse model was used in combination with PI-3065 to gain insights into the effect of PI3Kδ inhibition on MDSCs. Results PI-3065 treatment resulted in a concomitant reduction in MDSC expansion and tumour size. However, targeting Tregs independent of PI-3065 was also associated with reduced tumour volume and MDSC numbers. Surgical removal of tumours resulted in a rapid and significant decline in MDSC numbers, whilst ex vivo studies using cells from PI-3065-treated mice demonstrated no direct effect of the inhibitor on MDSC activity. Conclusions Our data suggest that MDSCs are not inhibited directly by PI-3065 treatment but that their reduced recruitment and immunosuppression within the tumour microenvironment is an indirect consequence of PI3Kδ-inhibition-driven tumour control. This indicates that PI3Kδ inhibition drives tumour immunity by breaking down multiple immunosuppressive pathways through both direct mechanisms (on Treg) and indirect mechanisms, secondary to tumour control (on MDSCs).

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Springer Nature [academic journals on nature.com]
ISSN:	0007-0920
Funders:	Wellcome Trust, Cancer Research UK
Date of First Compliant Deposit:	21 October 2022
Date of Acceptance:	12 July 2022
Last Modified:	20 Sep 2023 21:56
URI:	https://orca.cardiff.ac.uk/id/eprint/153601

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