Autoimmune melanocyte destruction is required for robust CD8+ memory T cell responses to mouse melanoma

Abstract

A link between autoimmunity and improved antitumor immunity has long been recognized, although the exact mechanistic relationship between these two phenomena remains unclear. In the present study we have found that vitiligo, the autoimmune destruction of melanocytes, generates self antigen required for mounting persistent and protective memory CD8 + T cell responses to melanoma. Vitiligo developed in approximately 60% of mice that were depleted of regulatory CD4 + T cells and then subjected to surgical excision of large established B16 melanomas. Mice with vitiligo generated 10-fold larger populations of CD8 + memory T cells specific for shared melanoma/melanocyte antigens. CD8 + T cells in mice with vitiligo acquired phenotypic and functional characteristics of effector memory, suggesting that they were supported by ongoing antigen stimulation. Such responses were not generated in melanocyte-deficient mice, indicating a requirement for melanocyte destruction in maintaining CD8 + T cell immunity to melanoma. Vitiligo-associated memory CD8 + T cells provided durable tumor protection, were capable of mounting a rapid recall response to melanoma, and did not demonstrate phenotypic or functional signs of exhaustion even after many months of exposure to antigen. This work establishes melanocyte destruction as a key determinant of lasting melanoma-reactive immune responses, thus illustrating that immune-mediated destruction of normal tissues can perpetuate adaptive immune responses to cancer.

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+T cells

“…In MT/ret mice, increased T-cell reactivity against melanoma antigens would, thus, be a consequence of vitiligo rather than its cause. In line with this explanation, Byrne et al have established that melanocyte destruction is crucial for inducing lasting melanomaspecific CD8 + T cell-mediated responses, thus illustrating that immune-mediated destruction of normal tissues can perpetuate adaptive immune responses to cancer (36).…”

Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes

“…In one study of a polyvalent melanoma cell vaccine in patients with melanoma, those with high TRP-2 antibody titers after treatment had improved survival compared with non-responders (40). In the murine model, vitiligo-affected hosts maintain gp100- and TRP2-specific memory CD8+ T-cells at 10x higher frequencies compared to unaffected hosts (41). …”

Autoimmune Vitiligo Does Not Require the Ongoing Priming of Naive CD8 T Cells for Disease Progression or Associated Protection against Melanoma

“…Our work has recently shown that vitiligo is also a key determinant for the generation of long-lived memory CD8 T cell responses to melanoma (5). We found that melanocyte antigens, which are liberated during the course of autoimmune vitiligo, are required to maintain non-exhausted and functional memory CD8 T cell responses against melanoma (5). Thus there exists a causal relationship between tissue-specific autoimmunity and the maintenance of immunity to cancer.…”

“…However, the ontogeny of melanocyte/melanoma antigen-specific T cells in hosts with vitiligo remains incompletely understood. While we have shown that vitiligo maintains populations of melanoma-primed CD8 T cells for many months as memory (5), it remains unclear whether the ongoing destruction of melanocytes also drives the continual priming of new T cells from the naïve pool. Such newly primed effectors could contribute to the pathogenesis of vitiligo and to melanoma tumor protection.…”