Immune profile associated to vitiligo onset in melanoma patients undergoing treatment with checkpoint inhibitors gives insight into the raising of the adverse event and of the effective anti-tumor response. Immune profile associated to vitiligo onset in melanoma patients undergoing treatment with checkpoint inhibitors gives insight into the raising of the adverse event and of the effective anti-tumor response

Immunotherapy with checkpoint inhibitors is an efficient treatment for metastatic melanoma. Development of vitiligo upon immunotherapy represents a specific immune-related adverse event (irAE) diagnosed in 15% of patients and associated with a positive clinical response. Therefore, a detailed characterization of immune cells during vitiligo onset in melanoma patients would give insight into the immune mechanisms mediating both this irAE and the anti-tumor response. To better understand these aspects, we analyzed T cell subsets from peripheral blood of metastatic melanoma patients undergoing treatment with anti-programmed cell death protein (PD)-1 antibodies. Stratification of patients for developing or not developing vitiligo during therapy revealed an association between blood reduction of mucosal associated invariant T (MAIT), T helper (h) 17, natural killer (NK) CD56bright, and T regulatory (T-reg) cells and vitiligo onset. To deeply characterize the tumoral T cell response concomitant to vitiligo onset, we analyzed T cell content in skin biopsies collected from melanoma patients who developed vitiligo. Consistently with the observed blood reduction of Th17 cells in melanoma patients developing vitiligo during immunotherapy, we found an enrichment of Th17 cells in the vitiligo skin biopsy, suggesting a migration of Th17 cells from the blood into the autoimmune lesion. To further characterize T cells in vitiligo skin lesion of melanoma patients, we sequenced T cell receptor (TCR) of cells derived from biopsies of vitiligo and primary melanoma of the same patient. Interestingly, we found different TCR sequences between vitiligo and primary melanoma lesions, except for a few cases showing the same TCR sequences. In contrast, shared TCR sequences were identified between vitiligo and metastatic tissues of the same patient. These data indicate that T cell response against normal melanocytes, which is involved in vitiligo onset, is not mainly mediated by the reactivation of specific T cell clones infiltrating primary melanoma but may be elicited by T cell clones targeting metastatic tissues. Altogether, our data indicate that anti-PD-1 therapy induces a de novo immune response, composed of different T cell subtypes, whose role may be related to the development of vitiligo and the response against metastatic tumor. Overall design: In this study we performed TCR-Seq of PBMC (10 biological replicateas), primary melanoma (15 biological replicates), metastasis (5 biological replicates) and vitiligo (10 biological replicates) samples deriving from patients affected by metastatic melanoma, who were treated with anti-PD1 immunotherapy at IDI-IRCCS. ***Submitter states that Adaptive Biotechnologies does not release raw data***