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To identify predictive biomarkers, we integrated bulk and single-cell RNA sequencing (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 nonresponders, tumors show evidence of increased tumor proliferation, neuronal stem cell markers, and IL1. Responders have increased type I\/II interferons and preexisting tissue resident (Trm) CD8 or V\u03b41 \u03b3\u03b4 T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of public T-cell receptors. Spatial transcriptomics demonstrated colocalization of T cells with B and dendritic cells, which supply chemokines and costimulation. Lastly, ICB significantly increased clonal expansion or recruitment of Trm and V\u03b41 cells in tumors specifically in responders, underscoring their therapeutic importance. These data identify potential clinically actionable biomarkers and therapeutic targets for MCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>MCC serves as a model of ICB response. We utilized the largest-to-date, multimodal MCC dataset (n = 116 patients) to uncover unique tumor-intrinsic properties and immune circuits that predict response. We identified CD8 Trm and V\u03b41 T cells as clinically actionable mediators of ICB response in major histocompatibility complex\u2013high and \u2013low MCCs, respectively.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-23-0798","type":"journal-article","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T08:55:26Z","timestamp":1721984126000},"page":"1631-1652","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Preexisting Skin-Resident CD8 and \u03b3\u03b4 T-cell Circuits Mediate Immune Response in Merkel Cell Carcinoma and Predict Immunotherapy Efficacy"],"prefix":"10.1158","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3310-0262","authenticated-orcid":false,"given":"Zachary Z.","family":"Reinstein","sequence":"first","affiliation":[{"name":"Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 1"},{"name":"Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 2"},{"name":"Center for Human Immunobiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 3"},{"name":"Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3148-8833","authenticated-orcid":false,"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 1"},{"name":"Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5986-4207","authenticated-orcid":false,"given":"Oscar E.","family":"Ospina","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5394-4774","authenticated-orcid":false,"given":"Matt D.","family":"Nichols","sequence":"additional","affiliation":[{"name":"Department of Tumor Metastasis and Microenvironment, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4001-2377","authenticated-orcid":false,"given":"Victoria A.","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 1"},{"name":"Robert H. 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