Pre-existing skin-resident CD8 and gd T cell circuits mediate immune response in Merkel cell carcinoma and predict immunotherapy efficacy.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ~50% response rate to immune checkpoint blockade (ICB) therapy. To identify predictive biomarkers, we integrated bulk and single-cell RNA-seq with spatial transcriptomics from a cohort of 186 samples from 116 patients, including bulk RNA-seq from 14 matched pairs pre- and post-ICB. In non-responders, tumors show evidence of increased tumor proliferation, neuronal stem cell markers, and IL-1. Responders have increased type I/II interferons and pre-existing tissue resident (Trm) CD8 or Vd1 gd T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of public TCRs. Spatial transcriptomics demonstrated co-localization of T cells with B and dendritic cells, which supply chemokines and co-stimulation. Lastly, ICB significantly increased clonal expansion or recruitment of Trm and Vd1 cells in tumors specifically in responders, underscoring their therapeutic importance. These data identify potential clinically actionable biomarkers and therapeutic targets for MCC.