Northwestern University Chicago, Illinois, United States
Abstract Text: Merkel cell carcinoma (MCC) is an uncommon, aggressive neuroendocrine skin carcinoma with two etiological subtypes. Polyomavirus-driven MCCs harbor public viral antigens, but few, if any, private somatic mutations, whereas UV-induced virus-negative MCCs harbor a nearly uniformly high tumor mutation burden. Both subtypes are immunogenic, with response rates equivalent to those of immune checkpoint blockade (ICB); thus, MCC is a powerful and unique human model for tumor immunotherapy. To identify biomarkers that predict response, we integrated bulk (n=65 patients) and single-cell RNA-seq (302,597 cells from 59 patients) and spatial transcriptomics (n=20 patients) from a cohort of 110 patients. Our dataset highlights the importance of pre-existing immune cells and cytokines in the MCC tumor microenvironment (TME). In non-responders, MCCs show evidence of increased tumor proliferation, which correlates with lower immune infiltration and increased IL-1. In responders, tumors have increased levels of 1) type I/II interferons, 2) tissue resident (Trm) CD8+ T cells, or Vδ1 γδ T cells in MHC class I low tumors. Multi-modal scRNA-seq analyses showed that CD8+ Trm and Vδ1 γδ cells functionally converge to generate antitumor immunity by acquiring overlapping antigen-specific transcriptional programs and clonal expansion of public TCRs that putatively recognize tumor antigens. Spatial transcriptomics demonstrated significant co-localization of T cells with B and dendritic cells, which supply chemokines and co-stimulation. Finally, in a subset of patients, Trm cells are clonally expanded after ICB, highlighting their therapeutic importance. Collectively, our unique dataset identified potentially clinically actionable cytokine circuits in human cancers.
