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.
Highlights
Melanoma is responsible for ~10,000 deaths in the United States and ~55,000 deaths worldwide each year, making it the cause of over 75% of skin cancer-related deaths [1, 2]
This early switch to glycolytic metabolism provides a source of carbon for the pentose phosphate pathway and tricarboxylic acid (TCA) cycle, both of which produce intermediates for fatty acid synthesis needed to support the expansion of membrane mass for the endoplasmic reticulum (ER) and Golgi apparatus, allowing dendritic cells (DCs) to meet the demands of protein synthesis, transport, and secretion that are associated with maturation/activation [146]
Feces from only one cluster of melanoma patients promoted colonization of immunogenic B. thetaiotaomicron and B. fragilis in mice, and these animals were the only fecal transplant recipients to mount effective antitumor responses following α-CTLA-4 Ab treatment. While these data suggest that the presence of commensal Bacteroides species in the gut may be a useful prognostic indicator for identifying patients most likely to benefit from checkpoint blockade therapy, it should be noted that confounding data on the influence of Bacteroides species on therapeutic efficacy in metastatic melanoma patients have emerged from recent clinical studies
Summary
Melanoma is responsible for ~10,000 deaths in the United States and ~55,000 deaths worldwide each year, making it the cause of over 75% of skin cancer-related deaths [1, 2]. Other next-generation vaccination approaches currently being explored include immunization with tumor-specific neoantigens (either alone or loaded onto DC) that promote responses against mutated tumor-specific epitopes [44,45,46] as well as maneuvers that induce local or systemic activation of endogenous, tumor Ag-presenting DC [47, 48] These next-generation DC-based vaccines and the ways in which they might be incorporated as part of combinatorial regimens into the current cancer immunotherapy landscape that is being dominated by checkpoint blockade and ACT therapies have recently been reviewed more thoroughly elsewhere [49]. INDUCTION OF IMMUNOGENIC CELL DEATH (ICD) AS A MEANS OF PROMOTING DC-MEDIATED ANTITUMOR IMMUNITY
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