Plasmacytoid Dendritic Cell Impairment in Metastatic Melanoma by Lactic Acidosis

Cancers

Raffaella Vescovi¹  Matilde Monti¹  Claudia Specchia¹  William Vermi¹  Daniele Moratto²  Alfredo Berruti³  Francesca Consoli³  Davide Farina⁴ 

[1] Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy;Laboratory of Genetic Disorders of Childhood, Angelo Nocivelli Institute for Molecular Medicine, ASST Spedali Civili di Brescia, 25123 Brescia, Italy;Oncology Unit, ASST Spedali Civili di Brescia, 25123 Brescia, Italy;Radiology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy;

关键词: plasmacytoid dendritic cells;    melanoma;    lactate dehydrogenase;    TLR;    interferon;    CXCL10;   

DOI  :  10.3390/cancers12082085

来源: DOAJ

【 摘 要 】

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 BRAF^V600+ 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.

【 授权许可】

Unknown