Preventing surgery-induced natural killer cell suppression and metastases by inhibiting PI3K-gamma signaling in myeloid-derived suppressor cells.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) have a dominating presence in the postoperative period, mediating the suppression of natural killer (NK) cells and promoting cancer metastases after surgery. However, their phenotype and effects on postoperative cellular immunity remain incompletely understood. This study aims to functionally characterize surgery-induced (sx) MDSCs and identify potential therapeutic strategies to mitigate their immunosuppressive effects. METHODS: We used multicolor flow cytometry to characterize sx-MDSCs from n=55 patients with cancer undergoing surgery at various time points. Furthermore, single-cell RNA sequencing was performed on a cohort of patients. Our functional ex vivo sx-MDSC:NK cell suppression assay was used to investigate the activity of sx-MDSCs and to screen a 147 small molecule library to identify sx-MDSC antagonists. Lastly, we used preclinical murine models of postoperative metastases to evaluate the therapeutic potential of the inhibitors identified. RESULTS: Sx-MDSCs significantly expanded after surgery and single-cell RNA sequencing identified signatures resembling immunosuppressive monocytes, including an upregulation of PI3K signaling. These sx-MDSCs also suppressed NK cell activity from patient samples and the small molecule screen identified PI3K-γ inhibitors as potent modulators of sx-MDSC activity. In our murine models, inhibiting PI3K-γ with specific inhibitors reduced postoperative metastases, further corroborating the role of this pathway in sx-MDSC-mediated immune suppression. CONCLUSIONS: Our findings highlight the critical role of PI3K-γ signaling in postoperative sx-MDSC-mediated immune suppression. Targeting this pathway with PI3K-γ inhibitors represents a promising therapeutic strategy to prevent NK cell suppression and reduce postoperative metastases.