The introduction of targeted
therapies and
immunotherapies has significantly improved the outcome of metastatic
melanoma (MM) patients. These approaches rely on immune functions for their anti-
melanoma response. Plasmacytoid dendritic cells (pDCs) exhibit anti-
tumor function by production of effector molecules,
type I interferons (I-IFNs), and
cytokines. Tissue and blood pDCs result compromised in MM, although these findings are still partially conflicting. This study reports that blood pDCs were dramatically depleted in MM, particularly in patients with high
lactate dehydrogenase (LDH) and high
tumor burden; the reduced pDC frequency was associated with poor overall survival. Circulating pDCs resulted also in significant impairment in
interferon alpha (IFN-α) and C-X-C motif
chemokine 10 (CXCL10) production in response to
toll-like receptor (TLR)-7/8 agonists; on the contrary, the response to TLR-9 agonist remained intact. In the BRAFV600+ subgroup, no recovery of pDC frequency could be obtained by BRAF and
MEK inhibitors (BRAFi; MEKi), whereas their function was partially rescued. Mechanistically, in vitro exposure to
lactic acidosis impaired both pDC viability and function. In conclusion, pDCs from MM patients were found to be severely impaired, with a potential role for
lactic acidosis. Short-term responses to treatments were not associated with pDC recovery, suggesting long-lasting effects on their compartment.