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

被引:8
|
作者
Lauder, Sarah N. [1 ]
Smart, Kathryn [1 ]
Bart, Valentina M. T. [1 ]
Pires, Ana [1 ]
Scott, Jake [1 ]
Milutinovic, Stefan [1 ]
Godkin, Andrew [1 ]
Vanhaesebroeck, Bart [2 ]
Gallimore, Awen [1 ]
机构
[1] Cardiff Univ, Sch Med, Div Infect & Immun, Cardiff CF14 4XN, Wales
[2] UCL, UCL Canc Inst, Paul OGorman Bldg,72 Huntley St, London WC1E 6BT, England
基金
英国惠康基金;
关键词
REGULATORY T-CELLS; IMMUNE TOLERANCE; ACTIVATION; EXPRESSION; ENABLES; MEDIATE;
D O I
10.1038/s41416-022-01917-0
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background Recent studies have demonstrated that blocking the PI3K delta 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 PI3K delta 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 PI3K delta-inhibition-driven tumour control. This indicates that PI3K delta 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).
引用
收藏
页码:1595 / 1602
页数:8
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