{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T12:00:59Z","timestamp":1785326459629,"version":"3.55.0"},"reference-count":82,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"unspecified","delay-in-days":28,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015979","name":"Pelotonia","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100015979","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,6,29]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Although chromosome 14q deletion (14q\u2212) is present in up to 40% of clear cell renal cell carcinoma (ccRCC) cases, its immunologic and molecular impact remains unclear. Because\n                      <jats:italic>TRAF3<\/jats:italic>\n                      and\n                      <jats:italic>NF\u039aBIA<\/jats:italic>\n                      , key regulators of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB) signaling, are located on 14q, we hypothesize that 14q\u2212 in ccRCC promotes increased inflammation and unique determinants of immune checkpoint blockade (ICB) response.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We collected data from 825 patients with ccRCC from publicly available sources, our own independent retrospective study, and the Oncology Research Information Exchange Network. These data include bulk RNA-sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), and whole exome sequencing (WES). We also include reverse phase protein array from DepMap cell lines (n=277). Next, we performed multiplex immunofluorescence for spatial analysis of immune cells on 23 patient slides with paired WES and ICB response. Finally, progression-free survival, 14q\u2212 status (assessed in bulk RNA-seq or whole exome sequencing), and kidney inflammatory marker\n                      <jats:italic>EDNRB<\/jats:italic>\n                      expression were assessed in two independent ICB immunotherapy trials.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      14q\u2212 status is associated with increased NF-\u03baB-target transcription and p65 phosphorylation. Tumor scRNA-seq revealed increased expression of\n                      <jats:italic>CCL20<\/jats:italic>\n                      , an NF-\u03baB target and lymphotactic protein. Simultaneously, single-cell and bulk RNA-seq demonstrated higher effector CD8+T\u2009cell infiltration in 14q- tumors compared with controls. We investigated myeloid panel mIF images from 14q\u2212 tumors and found dendritic cells (DCs) significantly aggregate with tumor cells in ICB responders compared with non-responders. Cell\u2013cell communication analysis on DCs and tumor cells from a 14q\u2212 responder revealed tumor-derived\n                      <jats:italic>EDN1<\/jats:italic>\n                      is uniquely interacting with\n                      <jats:italic>EDNRB<\/jats:italic>\n                      on DCs. In two ICB trials, 14q\u2212 combined with elevated\n                      <jats:italic>EDNRB<\/jats:italic>\n                      expression correlated with significantly improved progression-free survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This is the first evidence that 14q\u2212 in ccRCC is associated with an antitumor inflammatory phenotype, possibly driven by aberrant NF-\u03baB activation. Furthermore, 14q\u2212 with high\n                      <jats:italic>EDNRB<\/jats:italic>\n                      expression (\n                      <jats:italic>EDNRB<\/jats:italic>\n                      +) may serve as a predictive biomarker for ICB response in ccRCC. Finally, our results indicate patients with 14q\u2212\/\n                      <jats:italic>EDNRB<\/jats:italic>\n                      \u2212 may respond poorly to immunotherapy and new treatment options should be explored for this cohort.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-014201","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:10:25Z","timestamp":1785323425000},"page":"e014201","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omic characterization of 14q deletion in renal clear cell carcinoma identifies\n                    <i>EDNRB<\/i>\n                    as a predictor of immunotherapy response"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9630-3265","authenticated-orcid":false,"given":"Raven","family":"Vella","sequence":"first","affiliation":[{"name":"Department of 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