Tissue-specific programming of CD8 effector T cells in immune checkpoint inhibitor-associated vitiligo and anti-tumor immunity in melanoma.

Abstract

e21503 Background: Immune checkpoint inhibitor (ICI) therapy targeting PD-1 and CTLA-4 (e.g., ipilimumab-nivolumab) has revolutionized treatment of advanced melanoma. While there are few reliable predictors of response, ICI-associated vitiligo is a common immune-related adverse event in melanoma and is associated with favorable clinical outcomes. Understanding the immunological correlates of ICI-associated vitiligo may therefore provide crucial insights into the mechanisms underlying durable response to melanoma immunotherapy. Methods: We performed single-cell multiomic profiling (gene expression, CITE-seq, T cell receptor [TCR] sequencing) of matched primary tumor, lymph node metastasis, and vitiligo skin from a metastatic melanoma patient who both achieved durable response to ipilimumab-nivolumab and developed vitiligo. To contextualize these findings, we integrated ~57,000 T cells from publicly available single-cell datasets encompassing ICI-treated melanoma, autoimmune vitiligo, and healthy skin. Results: Across tissues and datasets, we identified six CD4⁺ and eight CD8⁺ T cell states conserved across conditions, though exhibiting tissue-specific abundance shifts. CD8⁺ T cell populations revealed the most pronounced differences, most notably demonstrating enrichment within vitiligo skin of a distinct MHC II-expressing CD8⁺ effector population with high expression of GZMA , GZMK , and GZMH , along with activation-associated programs suggesting recent TCR engagement and a non-terminal inflammatory effector state. Additional cytotoxic CD8⁺ subsets with checkpoint-associated and tissue-resident memory-like features were seen across tumor and skin, whereas CD4⁺ T cell states demonstrated more modest tissue-specific variation. In contrast, transcriptionally related CD8⁺ T cells within tumor exhibited characteristics suggesting functional limitation within the suppressive tumor microenvironment. Through leveraging paired single-cell TCR sequencing from the same patient, ongoing analyses are evaluating the clonal relationships between vitiligo- and tumor-infiltrating T cells to determine whether shared TCRs adopt divergent transcriptional programs across tissues. Conclusions: Our data support a framework whereby ICI-associated vitiligo reflects tissue-specific effector-state programming of melanoma-reactive CD8⁺ T cells, providing mechanistic insight into the link between treatment-induced autoimmunity and effective anti-tumor immunity.