Preventing surgery induced immune suppression and metastases by inhibiting PI3K-gamma signalling in Myeloid-Derived Suppressor Cells

Myeloid derived suppressor cells (MDSCs) have a dominating presence in the postoperative period and mediate the suppression of Natural Killer (NK) cells and promotion of cancer metastases after surgery. However, their functional characteristics and effect on cellular immunity after surgery have not been comprehensively investigated. Here, we characterize the expansion of surgery-induced (sx) MDSCs via multi-colour flow cytometry, single-cell RNA sequencing, and functional ex vivo NK cell suppression assays. We then screened a small molecule library using our sx-MDSC:NK cell suppression assay to identify compounds that could inhibit sx-MDSCs. These studies provide evidence that PI3K-γ signalling is upregulated in sx-MDSCs and blockade with PI3K-γ specific inhibitors attenuates NK cell suppression in humans and mice and reduces postoperative metastases in murine models. Upregulated PI3K-γ in sx-MDSCs is a potential pathway amenable to therapeutic targeting in the postoperative period. One Sentence Summary The suppressive mechanisms of surgery-induced myeloid derived suppressor cells use PI3K signalling and are amenable to PI3K-gamma specific inhibitors.