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We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response. We found that nivolumab durably induces a pro-inflammatory state within the primary tumor, and baseline immune infiltration within the primary tumor correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations.<\/jats:p>","DOI":"10.1038\/s41598-024-51889-9","type":"journal-article","created":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T21:02:39Z","timestamp":1705438959000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma"],"prefix":"10.1038","volume":"14","author":[{"given":"Nirmish","family":"Singla","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas R.","family":"Nirschl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandar Z.","family":"Obradovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Shenderov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara","family":"Lombardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaopu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Pons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelani C.","family":"Zarif","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven P.","family":"Rowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce J.","family":"Trock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans J.","family":"Hammers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trinity J.","family":"Bivalacqua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip M.","family":"Pierorazio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie S.","family":"Deutsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara L.","family":"Lotan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janis M.","family":"Taube","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasser M. 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Rowe: research funding and consulting agreement with Progenics Pharmaceuticals, Inc., Precision Molecular, Inc., PlenaryAI, Inc.; stock options in D&D Pharmatech. Hans J. Hammers: paid consultant\/advisor for ARMO Biosciences, Inc., Bayer AG, Bristol-Myers Squibb, Corvus Pharmaceuticals, Exelixis, Inc., Eli Lilly and Company, Merck & Co., Inc., Pfizer, Inc., Novartis International AG, and Surface Oncology, Inc.; research\/grant support from Bristol-Myers Squibb and Merck & Co., Inc. Tamara L. Lotan: research funding from DeepBio, AIRA Matrix and Exact Sciences. Janis M. Taube: paid consultant\/advisor for Akoya Biosciences, Inc., AstraZeneca, plc., Bristol-Myers Squibb, Compugen, Ltd., and Merck & Co., Inc.; equipment loan, reagent provision, and stock options with Akoya Biosciences, Inc. Yasser M. A. Ged: advisory board consultation fees from Bristol Meyer Squib, Exelixis, BostonGene, and Aveo. Michael A. Gorin: consultant for RSIP Vision, Corbin Clinical Resources (Perineologic), Blue Earth Diagnostics Limited, KOELIS, Inc., Point Biopharma, Merck, Ambu A\/S; speakers bureau and consult for Lantheus Holdings, Inc.; patent licenses for Precision Molecular. Charles G. Drake: employment at Janssen Pharmaceuticals, Inc.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1458"}}