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How MCPyV spatially modulates immune responses within the tumor microenvironment and how such are linked to patient outcomes remains unknown. We interrogated the cellular and transcriptional landscapes of 60 MCC-patients using a combination of multiplex proteomics,\n                  <jats:italic>in-situ<\/jats:italic>\n                  RNA-hybridization, and spatially oriented transcriptomics. We identified a spatial co-enrichment of activated CD8\n                  <jats:sup>+<\/jats:sup>\n                  T-cells and CXCL9\n                  <jats:sup>+<\/jats:sup>\n                  PD-L1\n                  <jats:sup>+<\/jats:sup>\n                  macrophages at the invasive front of virus-positive MCC. This spatial immune response pattern was conserved in another virus-positive tumor, HPV\n                  <jats:sup>+<\/jats:sup>\n                  head-and-neck cancer. Importantly, we show that virus-negativity correlated with high risk of metastasis through low CD8\n                  <jats:sup>+<\/jats:sup>\n                  T-cell infiltration and the enrichment of cancer-associated-fibroblasts at the tumor boundary. By contrast, responses to immune-checkpoint blockade (ICB) were independent of viral-status but correlated with the presence of a B-cell-enriched spatial contexts. Our work is the first to reveal distinct immune-response patterns between virus-positive and virus-negative MCC and their impact on metastasis and ICB-response.\n                <\/jats:p>","DOI":"10.1101\/2025.06.06.657162","type":"posted-content","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T20:30:22Z","timestamp":1749241822000},"source":"Crossref","is-referenced-by-count":5,"title":["Spatially organized inflammatory myeloid-CD8\n                  <sup>+<\/sup>\n                  T cell aggregates linked to Merkel-cell Polyomavirus driven Reorganization of the Tumor Microenvironment"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6720-7570","authenticated-orcid":false,"given":"Maximilian","family":"Haist","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8201-1621","authenticated-orcid":false,"given":"Magdalena","family":"Matusiak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7200-3222","authenticated-orcid":false,"given":"Yuqi","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Zimmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henner","family":"Stege","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim Noah","family":"Kempchen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Mitschke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Weidenthaler-Barth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham L.","family":"Barlow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friederike","family":"Rogall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Delgado Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc-A.","family":"Baertsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Albertini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa","family":"Gariglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Borgogna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yury","family":"Goltsev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Grabbe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9961-7673","authenticated-orcid":false,"given":"John W.","family":"Hickey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garry P.","family":"Nolan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025060909150431000_2025.06.06.657162v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.77"},{"key":"2025060909150431000_2025.06.06.657162v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.2781"},{"key":"2025060909150431000_2025.06.06.657162v1.3","doi-asserted-by":"publisher","DOI":"10.1126\/science.1152586"},{"key":"2025060909150431000_2025.06.06.657162v1.4","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-0864"},{"key":"2025060909150431000_2025.06.06.657162v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2016.10.028"},{"key":"2025060909150431000_2025.06.06.657162v1.6","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.1020805"},{"key":"2025060909150431000_2025.06.06.657162v1.7","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-13-0034"},{"key":"2025060909150431000_2025.06.06.657162v1.8","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-2244"},{"key":"2025060909150431000_2025.06.06.657162v1.9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.727626"},{"key":"2025060909150431000_2025.06.06.657162v1.10","doi-asserted-by":"crossref","unstructured":"Tan, Y. , et al. 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