Vitiligo and vitiligo-associated markers as indicators of response to immunological checkpoint inhibitors in cutaneous melanoma

Although development of immune checkpoint inhibitors (ICI) has revolutionized the treatment of metastatic melanoma, more than a half of treated patients experience disease progression during therapy. Cases of spontaneous vitiligo-like leukoderma (VLL) have been described in melanoma patients and have been associated with a favorable outcome. This VLL can also develop in melanoma patients subjected to immune therapies such as treatment with interleukin-2, tumor vaccines or ICI. However, no consensus has been reached regarding the development of VLL and improved overall survival, no immunological mechanisms have been clarifying that link VLL development and response to therapy with ICI, no biomarkers of response to therapy with ICI have been identified so far. Our studies intend to answer these open questions. Firstly, we evaluate the possible association between the onset of VLL during ICI treatment and a better prognosis. We identified 280 patients who had inoperable or metastatic melanoma and had undergone immune therapy with ICI in any line of treatment in the last 10 years in our Institute. Toxicities developed during ICI therapy were evaluated. The Cox proportional-hazard model was used to investigate the association between development of VLL, as an ICI-related toxicity, and the risk of mortality or time to next treatment. Our findings indicate that development of VLL can be considered a biomarker of a better outcome in patients treated with ICI. We then characterized the immunological response of patients to ICI therapy either analyzing the circulating immune cell subtypes from therapy initiation up to development of VLL or sequencing the T-cell receptor of T lymphocytes present in the melanoma primary lesion and in the VLL skin sample of the same patients. Considering that development of VLL represents both an adverse event of ICI therapy and a favorable prognostic factor for overall survival, we analyzed soluble biomarkers of vitiligo active phase to validate them as early indicators of response to ICI in metastatic melanoma. We found that serum levels of CD25 and CXCL9 before and during treatment could represent biomarkers of favorable outcome of melanoma patients to ICI therapy. On the other hand, an increase of serum level of CXCL11 after one month of therapy could be a biomarker of acquired resistance to therapy. Altogether, our data indicate a strong link between VLL onset and response to ICI therapy.