Strategies to Improve the Efficacy of Dendritic Cell-Based Immunotherapy for Melanoma

Abstract

Melanoma is a highly aggressive form of skin cancer that frequently metastasizes to vital organs, where it is often difficult to treat with traditional therapies such as surgery and radiation. In such cases of metastatic disease, immunotherapy has emerged in recent years as an exciting treatment option for melanoma patients. Despite unprecedented successes with immune therapy in the clinic, many patients still experience disease relapse, and others fail to respond at all, thus highlighting the need to better understand factors that influence the efficacy of antitumor immune responses. At the heart of antitumor immunity are dendritic cells (DCs), an innate population of cells that function as critical regulators of immune tolerance and activation. As such, DCs have the potential to serve as important targets and delivery agents of cancer immunotherapies. Even immunotherapies that do not directly target or employ DCs, such as checkpoint blockade therapy and adoptive cell transfer therapy, are likely to rely on DCs that shape the quality of therapy-associated antitumor immunity. Therefore, understanding factors that regulate the function of tumor-associated DCs is critical for optimizing both current and future immunotherapeutic strategies for treating melanoma. To this end, this review focuses on advances in our understanding of DC function in the context of melanoma, with particular emphasis on (1) the role of immunogenic cell death in eliciting tumor-associated DC activation, (2) immunosuppression of DC function by melanoma-associated factors in the tumor microenvironment, (3) metabolic constraints on the activation of tumor-associated DCs, and (4) the role of the microbiome in shaping the immunogenicity of DCs and the overall quality of anti-melanoma immune responses they mediate. Additionally, this review highlights novel DC-based immunotherapies for melanoma that are emerging from recent progress in each of these areas of investigation, and it discusses current issues and questions that will need to be addressed in future studies aimed at optimizing the function of melanoma-associated DCs and the antitumor immune responses they direct against this cancer.

Collapse of the Plasmacytoid Dendritic Cell Compartment in Advanced Cutaneous Melanomas by Components of the Tumor Cell Secretome

“…One of the main findings of this study was that the exposure of PDCs to SN-mel induced PDC apoptosis, even after depletion of the EV compartment, indicating that soluble components released by melanoma cells affected PDC survival, consistent with other DCs (48). Gangliosides from human melanoma impair DC differentiation and promote apoptosis of monocyte-derived DCs (34).…”

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

“…Cytotoxic T cells' transition from an anergic to a fully activated state relies on an accelerated glucose metabolism (97) and, in a glucose-restricted TME, cancer cells easily succeed in such metabolic competition (98). Dampening of lymphocyte proliferation and motility, cytokine production and cytotoxic activity ultimately leads to immunosuppression, as a result of the excess cancer cell-derived lactate that blocks lactate export by immune cells (99) and might be inclusively taken up by those cells, thus impairing their glycolysis-dependent activation (100). Lactate also mediates polarization of macrophages from an M1-(anti-tumoral type) to an M2-like phenotype (pro-tumoral type) (101, 102); induction of VEGF (vascular endothelial growth factor) expression has been linked to this pro-tumoral state (103).…”

Improving immunotherapy for colorectal cancer using dendritic cells combined with anti-programmed death-ligand in�vitro

“…DCs are potent antigen-presenting cells and critical for the activation of T cells (19). Suppression of DC functions in patients with cancer is thought to contribute to the inhibition of the protective immune response and enhanced disease progression (20). At present, there are few studies that have compared the expression level of PD-L1 in DCs between healthy donors and patients with cancer.…”