Prostaglandin D2 axis impairs immunity against melanoma via dendritic cells and γδ T cells in middle-aged mice

The risk of developing melanoma increases with age. Although immune checkpoint blockade (ICB) therapy has shown considerable success, a significant portion of melanoma patients either fail to respond to ICB or eventually develop resistance. This leads to the urgent need for exploring novel treatments. Phospholipase A2 group IID (PLA2G2D) is an inducible enzyme found in myeloid cells, especially in aging dendritic cells (DCs), that exert an immunosuppressive effect by producing anti- or proinflammatory small lipid molecules, including prostaglandin D2 (PGD2). An aging-related increase of PLA2G2D-PGD2 expression makes this signaling a promising target for treating aging-associated diseases. The overexpression of hematopoietic PGD2 synthase identified in both human and mouse melanoma tissue further highlights the potential of PLA2G2D-PGD2-targeting therapy. In this study, we show that the absence of PLA2G2D or the PGD2 receptor, PTGDR, restricts primary tumor growth and lung metastasis of subcutaneously implanted melanoma, as demonstrated using middle-aged Pla2g2d-/- and Ptgdr-/- mice. These therapeutic benefits are linked to increased tumor infiltration of activated γδ T cells, which can be amplified in B16F10-bearing wild-type mice through the adoptive transfer of Ptgdr-/- DCs. These tumor-restraining effects were also confirmed in DC-specific PTGDR-deficient (zDCcrePtgdrfloxp) mice. Mechanistically, the enhanced production of IL-1β by Ptgdr-/- DCs contributes to the activation and accumulation of γδ T cells in tumor tissue. In summary, our findings highlight the effectiveness of targeting the PLA2G2D-PGD2/PTGDR axis to reprogram aging dendritic cells, thereby inhibiting melanoma progression and presenting a promising therapeutic target, particularly for elderly patients.