Summary Polymorphonuclear myeloid derived suppressor cells (PMN-MDSC) are pathologically activated neutrophils that are critically important for the regulation of immune responses in cancer. They contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite the recent advances in understanding of the PMN-MDSC biology, the mechanisms responsible for pathological activation of neutrophils are not well defined, which limits selective targeting of these cells. Here, we report that mouse and human PMN-MDSC exclusively up-regulate fatty acid transporter protein 2 (FATP2). Over-expression of FATP2 in PMN-MDSC was controlled by GM-CSF, through the activation of STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSC. The main mechanism of FATP2 mediated suppressive activity involved uptake of arachidonic acid (AA) and synthesis of prostaglandin E2 (PGE2). The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSC and substantially delayed tumor progression. In combination with check-point inhibitors it blocked tumor progression in mice. Thus, FATP2 mediates acquisition of immune suppressive activity by PMN-MDSC and represents a new target to selectively inhibit the functions of PMN-MDSC and improve the effect of cancer therapy.

Highlights d The tumor microenvironment induces tumor cells to produce retinoic acid d Retinoic acid skews monocyte differentiation toward macrophage rather than DC d Blocking retinoic acid production enhances anti-tumor T cell immunity d Pharmacological blockade of retinoic acid signaling synergizes with anti-PD-1 therapy

Highlights d The transcription factor Spic restrains inflammatory responses in macrophages d Spic promotes the expression of the iron exporter ferroportin in activated macrophages d NF-kB activity is required for the expression of Spic in activated macrophages d Interferon-gamma suppresses Spic expression in activated macrophages

Macrophages in SHH subgroup medulloblastoma display dynamic heterogeneity that varies with treatment modality Graphical abstract Highlights d Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB) recruits diverse macrophages d Radiation or molecular-targeted therapy alters macrophage distribution in SHH-MB d Radiation recruits immunosuppressive monocyte-derived macrophages (TAMoMacs) in SHH-MB d Radiation-induced TAMoMacs regulate CD8 T cell and neutrophil numbers in SHH-MB