The immune system in pigment cell biology: villain or hero?

Abstract

Our understanding of pigment cell and melanoma biology is evolving rapidly. Major advances have been made by studying melanocytes and melanoma cells in vitro. Cell culture systems simplify the biology and provide much insight, but we must always be conscious that they do not fully recapitulate the complex interaction of pigment cells with their physiological environment, which includes keratinocytes, stromal cells, and extracellular matrix. One major feature that they inevitably omit is a functional immune system. In this issue of Pigment Cell & Melanoma Research, several manuscripts directly address the role that T lymphocytes play in pigment cell biology. A variety of immune checkpoints normally prevent immune attack of self-antigens. In vitiligo, the balance tips in favor of destruction, resulting in pathological loss of cutaneous melanocytes. In melanoma, local immune suppression appears to prevent immune destruction of melanoma cells, even when they express a variety of potentially immunogenic antigens. Occasionally, vitiligo can occur in the setting of patients with melanoma. In these cases, it is thought that autoimmune recognition of melanoma cells also results in destruction of cells with shared antigens, including normal cutaneous melanocytes. This observation, along with rare spontaneous remissions in patients with advanced-stage melanoma, has propelled melanoma into the forefront of research on tumor immunology. Early efforts with interleukin 2 treatment and adoptive transfer of autologous T cells have produced dramatic responses in a subset of patients with advanced-stage melanoma. More recent efforts have identified the regulation of T-cell costimulation as therapeutic target. Anti-CTLA4 therapy increased the median overall survival of patients and also increased the number of long-term melanoma survivors. Agents that block the PD-L1–PD-1 signaling axis also have produced promising patient responses. These successes in manipulating the immune system for clinical benefit have increased understanding of tumor and pigment cell immunology. However, this is a very difficult process to study in human patients for many reasons. There is significant variability in the individual host immune system. Also, in melanoma, the somatic genetics of the tumor is complex and variable. Sampling tissue at various time points during the process of immune-mediated destruction of pigment cells is likely to be crucial to understanding this process, yet is rarely possible to do in human patients due to ethical and practical considerations. Many efforts are underway to understand immune-mediated destruction of pigment cells and melanoma that look beyond the culture dish, including using mouse models to allow for functional evaluation of the mechanisms involved. For the sake of vitiligo patients and patients with melanoma, the hope is that increased understanding of the complex interaction between the immune system and pigment cells will result in future cures.