Plasmacytoid Dendritic Cell Impairment in Metastatic Melanoma by Lactic Acidosis

Abstract

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.

Prognostic value of lactate dehydrogenase for melanoma patients receiving anti-PD-1/PD-L1 therapy

“…Exposure of lactic acidosis to dendritic cells impaired both the viability and functions of dendritic cells. [ 61 ] Based on these findings, we speculate LDH may exert similar functions to the activation of PD-1/PD-L1 pathway and therefore, the presence of a high LDH level in melanomas may antagonize the therapeutic effects of PD-1/PD-L1 inhibitors and lead to a poor prognosis.…”

Prognostic value of neutrophil-lymphocyte ratio and lactate dehydrogenase in melanoma patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis

“…Increased lactic acidosis can compromise both the numbers and functions of dendritic cells. [ 81 ] Qiao et al [ 82 ] evaluated the efficacy of using LDH inhibitor oxamate and pembrolizumab alone or in combination in an NSCLC humanized mouse model. They found that both oxamate and pembrolizumab monotherapy significantly delayed tumor growth.…”

Lactate-Dependent Regulation of Immune Responses by Dendritic Cells and Macrophages

“…DCs and macrophages exposed to TLR-ligands produce markedly higher levels of proinflammatory cytokines and type-I interferons (IFN). In contrast, lactate-conditioned DCs and macrophages do not release immunostimulatory cytokines; instead, they express higher levels of IL-10 in response to TLR ligands ( 53 – 55 , 57 , 58 ). The TME contains higher levels of immune regulatory factors such as IL-10, retinoic acid (RA), and TGF-β that actively suppress differentiation and expansion of tumor-specific effector T cells ( 114 , 115 ).…”