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However, the relationship between the TME, usually characterized by immune cell density, and response to ICI is unclear. Here, we quantify the TME immune cell densities and spatial relationships (SRs) of 24 baseline UC samples, obtained before pre-operative combination ICI treatment, using multiplex immunofluorescence. We describe SRs by approximating the first nearest-neighbor distance distribution with a Weibull distribution and evaluate the association between TME metrics and ipilimumab+nivolumab response. Immune cell density does not discriminate between response groups. However, the Weibull SR metrics of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells or macrophages to their closest cancer cell positively associate with response. CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells close to B cells are characteristic of non-response. We validate our SR response associations in a combination ICI cohort of head and neck tumors. Our data confirm that SRs, in contrast to density metrics, are strong biomarkers of response to pre-operative combination ICIs.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-46450-1","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T13:01:46Z","timestamp":1711026106000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Spatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0643-6676","authenticated-orcid":false,"given":"Alberto","family":"Gil-Jimenez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"van Dijk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8318-5455","authenticated-orcid":false,"given":"Joris L.","family":"Vos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoni","family":"Lubeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurits L.","family":"van Montfoort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2931-3097","authenticated-orcid":false,"given":"Dennis","family":"Peters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4482-2191","authenticated-orcid":false,"given":"Erik","family":"Hooijberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annegien","family":"Broeks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1777-012X","authenticated-orcid":false,"given":"Charlotte L.","family":"Zuur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bas W. 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LFAW received research funding from Genmab, which was all paid to the Netherlands Cancer Institute. CLZ received research financial support from Bristol Myers Squibb to fund the IMCISION trial, which was all paid to the Netherlands Cancer Institute. The rest of the authors have no conflicts of interest related to this work.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2538"}}