Abstract
Melanoma-associated vitiligo is the best-studied example of the linkage between tumor immunity and autoimmunity. Although vitiligo is an independent positive prognostic factor for melanoma patients, the autoimmune destruction of melanocytes was long thought to be merely a side effect of robust anti-tumor immunity. However, new data reveal a key role for vitiligo in supporting T cell responses to melanoma. This research perspective reviews the history of melanoma-associated vitiligo in patients, the experimental studies that form the basis for understanding this relationship, and the unique characteristics of melanoma-specific CD8 T cells found in hosts with vitiligo. We also discuss the implications of our recent findings for the interpretation of patient responses, and the design of next-generation cancer immunotherapies.
Highlights
The past several decades of research in tumor immunology have revealed a strong link between tumor immunity and autoimmunity
Following Treg depletion, we showed that surgical excision of intradermal B16 melanoma tumors resulted in a majority of mice developing CD8 T cell-mediated vitiligo [9, 63]
In B16 tumor-bearing mice treated by surgery and a stimulatory mAb against the glucocorticoidinduced TNFR family-related receptor (GITR), we found that protective T cell responses are preferentially directed against tumor-specific antigens [78]
Summary
The past several decades of research in tumor immunology have revealed a strong link between tumor immunity and autoimmunity. Adoptive transfers of low numbers of naïve TRP1-specific T cells into wild-type mice results in overt vitiligo and potent rejection of established B16 melanoma when given in combination with vaccine and IL-2 [52], irradiation and anti-CTLA-4 [73], or in lymphopenic hosts [72] Taken together, these TCR Tg models suggest that the development of spontaneous vitiligo in unmanipulated hosts may be dependent on TCR avidity for self-peptide/ MHC. In studies investigating CD8 T cell responses generated by Treg depletion and surgery in mice bearing B16-OVA tumors, we found that OVA-specific CD8 T cells develop into a small but functional memory T cell population, with a predominantly TCM phenotype [9] This was true regardless of the vitiligo status of the host [9]. Future investigation of melanoma/melanocyte antigen-specific T cells in surviving vitiligo-affected and unaffected patients should provide further insights into the types of T cell memory that mediate tumor protection in humans. Specific attributes of tissue-specific and non-specific autoimmune disease that contribute to anti-tumor immunity are only beginning to be understood, and will require future investigation
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