New perspectives on the role of vitiligo in immune responses to melanoma

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.

Figure 1. Vitiligo initiation at site of surgery

Mice bearing intradermal B16 tumors on the right flank were treated by anti-CD4 monoclonal antibody to deplete regulatory T cells, followed by surgical tumor excision, as we have previously described [63]. 3 weeks after surgery, vitiligo was observed along the surgical incision line (dotted line), and at points where surgical clips had pierced the skin (arrows).

Figure 2. Wsh mice as a model of vitiligo insufficiency

A vitiligo affected mouse (left) and a Wsh mouse (right).

Figure 3. Pathways to protective memory CD8 T cell responses to melanoma

(Top) Generation of CD8 T cell responses to shared melanoma/melanocyte antigens. Factors that contribute to priming of are listed at left. One or more of these factors leads to the breaking of tolerance (indicated by red line), resulting in effective primary CD8 T cell responses against melanoma that cross-react against healthy melanocytes and induce vitiligo during the effector phase. Ongoing melanocyte destruction provides antigen to support the memory phase of the response; unique characteristics of vitiligo-dependent memory T cells are indicated at right. (Bottom) Generation of CD8 T cell responses against tumor-specific antigens expressed by melanoma. Factors contributing to priming are listed at left; there is no need to overcome tolerance to generate primary CD8 T cell responses against tumor-specific antigens. In the effector phase, CD8 T cells directed against tumor-specific antigens kill melanoma cells but do not cross-react with melanocytes, therefore vitiligo does not occur. During the memory phase, CD8 T cells directed against tumor specific antigens possess classical memory T cell characteristics, indicated at right.