Dendritic Cell Subsets in Melanoma: Pathophysiology, Clinical Prognosis and Therapeutic Exploitation

SIMPLE SUMMARY: The clinical success of immunotherapies using immune checkpoint blockers deployed in melanoma strongly supports that the immune system can efficiently control tumor development in the long term. Yet, despite unprecedented successes, many patients still experienced relapse or failed to respond, highlighting the need to further explore the immune system interactions with tumor cells to develop efficient immunotherapeutic strategies. Since their discovery barely 50 years ago, dendritic cells (DCs) emerged as central regulators of immune responses. The DCs are active players in orchestrating anti-tumor responses but remain enigmatic as they harbor both anti-tumor and pro-tumor functions. This review aims to give an overview of the diversity of DC subsets, decipher their pathophysiology in melanoma patients and their impact on clinical outcome, the mechanisms by which tumors hijack DCs, and of their exploitation for therapeutic developments. Altogether, DCs hold great promise to participate in achieving better clinical outcomes for the patients in the future. ABSTRACT: Evasion from immunity is a hallmark of cancer development. Dendritic cells (DCs) are strategic immune cells shaping anti-tumor immune responses, but tumor cells exploit DC versatility to subvert their functions. Unveiling the puzzling role of DCs in the control of tumor development and mechanisms of tumor-induced DC hijacking is critical to optimize current therapies and to design future efficient immunotherapies for melanoma. Dendritic cells, crucially positioned at the center of anti-tumor immunity, represent attractive targets to develop new therapeutic approaches. Harnessing the potencies of each DC subset to trigger appropriate immune responses while avoiding their subversion is a challenging yet promising step to achieve tumor immune control. This review focuses on advances regarding the diversity of DC subsets, their pathophysiology and impact on clinical outcome in melanoma patients. We provide insights into the regulation mechanisms of DCs by the tumor, and overview DC-based therapeutic developments for melanoma. Further insights into DCs’ diversity, features, networking, regulation and shaping by the tumor microenvironment will allow designing novel effective cancer therapies. The DCs deserve to be positioned in the current melanoma immunotherapeutic landscape. Recent discoveries strongly motivate exploitation of the exceptional potential of DCs to drive robust anti-tumor immunity, offering promising tracks for clinical successes.