{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:21:55Z","timestamp":1785410515542,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,7]]},"group-title":"Cancer Biology","reference-count":35,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"United States Department of Defense","doi-asserted-by":"crossref","award":["HT94252510612"],"award-info":[{"award-number":["HT94252510612"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"crossref"}]},{"award":["P30CA014520"],"award-info":[{"award-number":["P30CA014520"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Clear cell renal cell carcinoma (ccRCC) exhibits heterogeneity in immune infiltration and clinical outcomes, but the mechanisms governing recruitment and organization of tumor-reactive CD8\u207a T cells remain incompletely defined. We investigated the role of the CXCL13\u2013CXCR5 axis in shaping CD8\u207a T cell recruitment, differentiation, and immune organization in high-risk, non-metastatic ccRCC. Human tumor, plasma, and matched adjacent kidney specimens were analyzed using ELISA, quantitative PCR, migration assays, multiplex immunofluorescence, single-cell RNA sequencing, spatial transcriptomics, and a syngeneic mouse model. CXCL13 was among the most upregulated chemokines in ccRCC relative to matched normal kidney and was embedded within a CD8\u207a T cell-associated inflammatory transcriptional program. In transwell and microphysiological system (MPS) assays, CXCL13 promoted CD8\u207a T cell migration, enriched CXCR5\u207a cells among migrating CD8\u207a T cells and showed reduced migration after CXCL13 or CXCR5 blockade. Single-cell analyses identified\n                  <jats:italic>CXCR5<\/jats:italic>\n                  expression within stem-like CD8\u207a T cell states associated with\n                  <jats:italic>TCF7<\/jats:italic>\n                  and\n                  <jats:italic>IL7R<\/jats:italic>\n                  , whereas\n                  <jats:italic>CXCL13<\/jats:italic>\n                  associated with later cytotoxic\/exhausted states along a continuous differentiation landscape. Spatial transcriptomics demonstrated that stem-like CD8\u207a T cells localized within structured lymphoid aggregates enriched for B cells, coordinated CXCL13\/CXCR5 expression, and signaling programs.\n                  <jats:italic>In vivo<\/jats:italic>\n                  , tumor-derived CXCL13 suppressed tumor growth, increased intratumoral CD8\u207a T cell infiltration, and enriched CXCR5\u207aTCF1\u207aCD8\u207a stem-like T cells. In human tumors, higher CXCL13 expression correlated with increased CXCR5\u207aCD8\u207a T cell infiltration and improved recurrence-free survival. These findings identify CXCL13 as a regulator of immune recruitment and niche organization and support the CXCL13\u2013CXCR5 axis as a biomarker and possible therapeutic target in ccRCC.\n                <\/jats:p>","DOI":"10.64898\/2026.05.04.722710","type":"posted-content","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T22:40:13Z","timestamp":1778193613000},"source":"Crossref","is-referenced-by-count":0,"title":["CXCL13-CXCR5 Signaling in CD8\u207a T Cell Recruitment and Lymphoid Immune Organization in Clear Cell Renal Cell Carcinoma"],"prefix":"10.64898","author":[{"given":"Daniel D.","family":"Shapiro","sequence":"first","affiliation":[{"name":"Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kye D.","family":"Nichols","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moon Hee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6505-8308","authenticated-orcid":false,"given":"Pavlos","family":"Msaouel","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanshan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zong","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla","family":"Esbona","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshi","family":"Kinoshita","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paz","family":"Lotan","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel F.","family":"Roadman","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Everlyne","family":"Nkadori","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie M.","family":"McGregor","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0415-9006","authenticated-orcid":false,"given":"David J.","family":"Beebe","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"name":"Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheena C.","family":"Kerr","sequence":"additional","affiliation":[{"name":"Carbone Cancer Center, 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