Plasmacytoid dendritic cells are the most efficient producers of
type I interferons, viz. IFNα, in the body and thus have the ability to influence anti-
tumor immune responses. But repression of effective intra-tumoral pDC activation is a key immuno-evasion strategy exhibited in
tumors-
tumor-recruited pDCs are rendered "tolerogenic," characterized by deficiency in IFNα induction and ability to expand regulatory T cells in situ. But the
tumor-derived factors that drive this functional reprogramming of intra-tumoral pDCs are not established. In this study we aimed at exploring if intra-tumoral abundance of the oncometabolite
lactate influences intra-tumoral pDC function. We found that
lactate attenuates IFNα induction by pDCs mediated by intracellular Ca2+ mobilization triggered by cell surface GPR81 receptor as well as directly by cytosolic import of
lactate in pDCs through the cell surface monocarboxylate transporters, affecting cellular metabolism needed for effective pDC activation. We also found that
lactate enhances
tryptophan metabolism and
kynurenine production by pDCs which contribute to induction of FoxP3+ CD4+ regulatory T cells, the major immunosuppressive immune cell subset in tumor microenvironment. We validated these mechanisms of
lactate-driven pDC reprogramming by looking into
tumor recruited pDCs isolated from patients with breast
cancers as well as in a preclinical model of
breast cancer in mice. Thus, we discovered a hitherto unknown link between intra-tumoral abundance of an oncometabolite resulting from metabolic adaptation in
cancer cells and the pro-
tumor tolerogenic function of
tumor-recruited pDCs, revealing new therapeutic targets for potentiating anti-
cancer immune responses.