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.
Highlights
The prognosis of metastatic melanoma (MM) patients has been dramatically improved by novel therapeutic strategies including targeted therapies and immune checkpoint blockades (ICB) [1,2].more than half of melanoma patients harbor BRAF mutation, together with the corresponding downstream signal transduction in the MAPK pathway [3]
Patients. Plasmacytoid dendritic cells (pDCs) from MM patients are severely impaired in their frequency and function, with a potential role for lactic acidosis
The frequency of circulating pDCs is dramatically reduced in melanoma patients with systemic spread [29,52,53], but their clinical significance as well as their functional state have been poorly characterized [35]
Summary
The prognosis of metastatic melanoma (MM) patients has been dramatically improved by novel therapeutic strategies including targeted therapies and immune checkpoint blockades (ICB) [1,2].more than half of melanoma patients (about 50–60%) harbor BRAF mutation, together with the corresponding downstream signal transduction in the MAPK (mitogen-activated protein kinase) pathway [3]. The prognosis of metastatic melanoma (MM) patients has been dramatically improved by novel therapeutic strategies including targeted therapies and immune checkpoint blockades (ICB) [1,2]. The development of high selective targeted agents such as vemurafenib or dabrafenib has dramatically improved overall survival (OS), progression-free survival (PFS), and response rate in BRAFV600+ advanced melanoma patients, in comparison to standard chemotherapy [4,5]. Anti-PD-1 agents such as nivolumab and pembrolizumab improve PFS and OS in comparison to ipilimumab, with an objective response rate of about 40% [6,8]. Anti-PD-1 treatments are considered an effective option in advanced melanoma patients, regardless of BRAF mutation [9]
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