{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T19:16:21Z","timestamp":1788376581692,"version":"build-2803163510"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":5,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Lymphocyte activation gene-3 (LAG-3) is an immune checkpoint receptor that has emerged as a biomarker of interest but its relationship with outcomes in renal cell carcinoma (RCC) is poorly characterized. This study evaluates molecular and immune correlates of LAG-3 expression and its association with outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>De-identified DNA-NGS data (xT) and RNA-NGS (xR) from patients (pts) with RCC (n\u2009=\u2009566) within the Tempus multi-modal database were analyzed using Lens. Eligible pts had first-line (1\u2009L) immunotherapy (IO) and biopsies collected within 1\u2009year of IO. Samples were stratified into 4 quartiles by LAG-3 RNA expression (TPM). Immune cell proportions were estimated from RNA (quanTIseq). Real-world objective response rate (rwORR) was assessed within 90 days of IO. Real-world overall survival (rwOS), defined as time from 1\u2009L IO start to death, lost to follow-up, or 5\u2009years after 1\u2009L, was analyzed using Cox proportional hazard models and P-values (Wald test).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The median age was 61 and majority were male (72%), white (79%), with metastases at specimen collection (94%). BAP1 (P\u2009=\u2009.008) and NF2 (P\u2009=\u2009.015) were increased in the highest LAG-3 groups, while VHL, PBMR1, and SETD2 were not. LAG-3 correlated with higher CTLA4, PD1, PD-L1, PD-2, TIM3, and TIGIT RNA expression (all P\u2009&amp;lt;\u2009.001), and increased M1\/M2 macrophages, NK, B, CD8 T, and Treg cell % (all P\u2009&amp;lt;\u2009.001). Higher LAG-3 expression was associated with improved rwORR and lower disease progression (P\u2009=\u2009.039). rwOS was not statistically significant (P\u2009=\u2009.2).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>LAG-3 is associated with distinct tumor immune features and may serve as a biomarker for early IO response in RCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/oncolo\/oyag317","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T11:40:16Z","timestamp":1786448416000},"source":"Crossref","is-referenced-by-count":0,"title":["Molecular and immune correlates of lymphocyte activation gene-3 expression in renal cell carcinoma"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3006-3390","authenticated-orcid":false,"given":"Harshitha","family":"Dudipala","sequence":"first","affiliation":[{"name":"Moores Cancer Center, University of California San Diego , La Jolla, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5783-3781","authenticated-orcid":false,"given":"Adam J","family":"Dugan","sequence":"additional","affiliation":[{"name":"Tempus AI, Inc. , Chicago, IL 60654,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Unnati","family":"Jariwala","sequence":"additional","affiliation":[{"name":"Tempus AI, Inc. , Chicago, IL 60654,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karyn","family":"Ronski","sequence":"additional","affiliation":[{"name":"Tempus AI, Inc. , Chicago, IL 60654,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Mercer","sequence":"additional","affiliation":[{"name":"Tempus AI, Inc. , Chicago, IL 60654,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddy","family":"Saad","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute , Boston, MA 02215,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jad El","family":"Masri","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute , Boston, MA 02215,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6708-9922","authenticated-orcid":false,"given":"Marc","family":"Machaalani","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute , Boston, MA 02215,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Saleh","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute , Boston, MA 02215,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7116-334X","authenticated-orcid":false,"given":"Kayla Viets","family":"Layng","sequence":"additional","affiliation":[{"name":"Tempus AI, Inc. , Chicago, IL 60654,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7828-8646","authenticated-orcid":false,"given":"Yingying","family":"Yu","sequence":"additional","affiliation":[{"name":"Tempus AI, Inc. , Chicago, IL 60654,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5000-9105","authenticated-orcid":false,"given":"Sabina","family":"Signoretti","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute , Boston, MA 02215,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Braun","sequence":"additional","affiliation":[{"name":"Yale Cancer Center , New Haven, CT 06510,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumanta K","family":"Pal","sequence":"additional","affiliation":[{"name":"City of Hope Comprehensive Cancer Center , Duarte, CA 91010,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9201-3217","authenticated-orcid":false,"given":"Toni K","family":"Choueiri","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute , Boston, MA 02215,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana R","family":"McKay","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California San Diego , La Jolla, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"2026090214415871500_oyag317-B1","first-page":"1","article-title":"Surveillance strategies for renal cell carcinoma patients following nephrectomy","volume":"8","author":"Chin","year":"2006","journal-title":"Rev Urol"},{"key":"2026090214415871500_oyag317-B2","doi-asserted-by":"publisher","first-page":"1889","DOI":"10.1007\/s11864-023-01161-5","article-title":"Treatment landscape of renal cell carcinoma","volume":"24","author":"Chen","year":"2023","journal-title":"Curr Treat Options Oncol"},{"key":"2026090214415871500_oyag317-B3","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1056\/NEJMoa1712126","article-title":"Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma","volume":"378","author":"Motzer","year":"2018","journal-title":"N Engl J Med"},{"key":"2026090214415871500_oyag317-B4","doi-asserted-by":"publisher","first-page":"e70052","DOI":"10.3322\/caac.70052","article-title":"Advanced urologic cancer consensus conference (AUC3) 2025: expert consensus on the management of renal cell and urinary tract cancers","volume":"76","author":"McKay","year":"2026","journal-title":"CA Cancer J Clin"},{"key":"2026090214415871500_oyag317-B5","doi-asserted-by":"publisher","first-page":"2500","DOI":"10.1056\/NEJMc1713444","article-title":"Tumor mutational burden and response rate to PD-1 inhibition","volume":"377","author":"Yarchoan","year":"2017","journal-title":"N Engl J Med"},{"key":"2026090214415871500_oyag317-B6","doi-asserted-by":"publisher","first-page":"TPS274","DOI":"10.1200\/JCO.2025.43.5_suppl.TPS274","article-title":"Prostate cancer real world evidence registry (PROCARE): recurrent and metastatic prostate cancer","volume":"43","author":"Hadaschik","year":"2025","journal-title":"JCO"},{"key":"2026090214415871500_oyag317-B7","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/s41591-025-04067-x","article-title":"Soluble MAdCAM-1 as a biomarker in metastatic renal cell carcinoma","volume":"32","author":"Alves Costa Silva","year":"2026","journal-title":"Nat Med"},{"key":"2026090214415871500_oyag317-B8","doi-asserted-by":"publisher","first-page":"5392","DOI":"10.4049\/jimmunol.169.10.5392","article-title":"Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3","volume":"169","author":"Workman","year":"2002","journal-title":"J Immunol"},{"key":"2026090214415871500_oyag317-B9","doi-asserted-by":"publisher","first-page":"5450","DOI":"10.4049\/jimmunol.172.9.5450","article-title":"Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo","volume":"172","author":"Workman","year":"2004","journal-title":"J Immunol"},{"key":"2026090214415871500_oyag317-B10","doi-asserted-by":"publisher","first-page":"1891","DOI":"10.1158\/2326-6066.CIR-19-0146","article-title":"PD-1 and LAG-3 dominate checkpoint receptor-mediated T-cell inhibition in renal cell carcinoma","volume":"7","author":"Zelba","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"2026090214415871500_oyag317-B11","doi-asserted-by":"publisher","first-page":"107241","DOI":"10.1016\/j.jbc.2024.107241","article-title":"The immune checkpoint receptor LAG3: structure, function, and target for cancer immunotherapy","volume":"300","author":"Mariuzza","year":"2024","journal-title":"J Biol Chem"},{"key":"2026090214415871500_oyag317-B12","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1084\/jem.20112533","article-title":"Agammaglobulinemia and absent B lineage cells in a patient lacking the p85alpha subunit of PI3K","volume":"209","author":"Conley","year":"2012","journal-title":"J Exp Med"},{"key":"2026090214415871500_oyag317-B13","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1038\/s41587-019-0259-z","article-title":"Integrated genomic profiling expands clinical options for patients with cancer","volume":"37","author":"Beaubier","year":"2019","journal-title":"Nat Biotechnol"},{"key":"2026090214415871500_oyag317-B14","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1007\/s00262-022-03252-y","article-title":"Comparison of the tumor immune microenvironment and checkpoint blockade biomarkers between stage III and IV non-small cell lung cancer","volume":"72","author":"Gao","year":"2023","journal-title":"Cancer Immunol Immunother"},{"key":"2026090214415871500_oyag317-B15","volume-title":"Survminer: Drawing Survival Curves using\u2019ggplot2'","author":"Kassambara","year":"2016"},{"key":"2026090214415871500_oyag317-B16","first-page":"189","volume-title":"Data Analysis, in ggplot2: Elegant Graphics for Data Analysis","author":"Wickham","year":"2016"},{"key":"2026090214415871500_oyag317-B17","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat Immunol"},{"key":"2026090214415871500_oyag317-B18","doi-asserted-by":"publisher","first-page":"e30852","DOI":"10.1371\/journal.pone.0030852","article-title":"Extended co-expression of inhibitory receptors by human CD8 T-cells depending on differentiation, antigen-specificity and anatomical localization","volume":"7","author":"Baitsch","year":"2012","journal-title":"PLoS One"},{"key":"2026090214415871500_oyag317-B19","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1016\/j.ccell.2014.10.018","article-title":"The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function","volume":"26","author":"Johnston","year":"2014","journal-title":"Cancer Cell"},{"key":"2026090214415871500_oyag317-B20","doi-asserted-by":"publisher","first-page":"6682","DOI":"10.1073\/pnas.1420370112","article-title":"Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses","volume":"112","author":"Liu","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026090214415871500_oyag317-B21","doi-asserted-by":"publisher","first-page":"10224","DOI":"10.29011\/2574-710x.10224","article-title":"Differences in co-expression of T cell co-inhibitory and co-stimulatory molecules with PD-1 across different human cancers","volume":"9","author":"Tarhini","year":"2024","journal-title":"J Oncol Res Ther"},{"key":"2026090214415871500_oyag317-B22","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-008293","article-title":"Treatment-free survival outcomes from the phase II study of nivolumab and salvage nivolumab\/ipilimumab in advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort a).","volume":"12","author":"Atkins","year":"2024","journal-title":"J Immunother Cancer"},{"key":"2026090214415871500_oyag317-B23","doi-asserted-by":"publisher","first-page":"102181","DOI":"10.1016\/j.clgc.2024.102181","article-title":"Phase II trial of intermittent therapy in patients with metastatic renal cell carcinoma treated with front-line ipilimumab and nivolumab","volume":"22","author":"Ornstein","year":"2024","journal-title":"Clin Genitourin Cancer"},{"key":"2026090214415871500_oyag317-B24","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1200\/JCO.20.02363","article-title":"Open-label, single-arm phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced clear cell renal cell carcinoma","volume":"39","author":"McDermott","year":"2021","journal-title":"J Clin Oncol"},{"key":"2026090214415871500_oyag317-B25","doi-asserted-by":"publisher","first-page":"116930","DOI":"10.1016\/j.biopha.2024.116930","article-title":"Macrophage polarization in the tumor microenvironment: emerging roles and therapeutic potentials","volume":"177","author":"Zhang","year":"2024","journal-title":"Biomed Pharmacother"},{"key":"2026090214415871500_oyag317-B26","doi-asserted-by":"publisher","first-page":"1655176","DOI":"10.3389\/fimmu.2025.1655176","article-title":"Tumor-infiltrating lymphocytes and tumor-associated macrophages in cancer immunoediting: a targetable therapeutic axis","volume":"16","author":"Mukherjee","year":"2025","journal-title":"Front Immunol"},{"key":"2026090214415871500_oyag317-B27","doi-asserted-by":"publisher","first-page":"1621812","DOI":"10.3389\/fimmu.2025.1621812","article-title":"The tumor immune microenvironment: implications for cancer immunotherapy, treatment strategies, and monitoring approaches","volume":"16","author":"Racacho","year":"2025","journal-title":"Front Immunol"},{"key":"2026090214415871500_oyag317-B28","doi-asserted-by":"publisher","first-page":"e109080","DOI":"10.1371\/journal.pone.0109080","article-title":"Lymphocyte activation gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed in vivo","volume":"9","author":"Durham","year":"2014","journal-title":"PLoS One"},{"key":"2026090214415871500_oyag317-B29","doi-asserted-by":"publisher","first-page":"100672","DOI":"10.1016\/j.jtocrr.2024.100672","article-title":"BAP1 deficiency inflames the tumor immune microenvironment and is a candidate biomarker for immunotherapy response in malignant pleural mesothelioma","volume":"5","author":"Xu","year":"2024","journal-title":"JTO Clin Res Rep"},{"key":"2026090214415871500_oyag317-B30","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1007\/s13402-024-00978-y","article-title":"Loss of histone deubiquitinase Bap1 triggers anti-tumor immunity","volume":"48","author":"Chang","year":"2025","journal-title":"Cell Oncol (Dordr)"},{"key":"2026090214415871500_oyag317-B31","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.molimm.2025.12.013","article-title":"Hippo signaling as a therapeutic switch for T cell functions and tumor immunity","volume":"190","author":"Fan","year":"2026","journal-title":"Mol Immunol"}],"container-title":["The Oncologist"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/oncolo\/advance-article-pdf\/doi\/10.1093\/oncolo\/oyag317\/70609418\/oyag317.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/31\/9\/oyag317\/70609418\/oyag317.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/oncolo\/article-pdf\/31\/9\/oyag317\/70609418\/oyag317.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T18:42:04Z","timestamp":1788374524000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/oncolo\/article\/doi\/10.1093\/oncolo\/oyag317\/8758886"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":31,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,8,6]]}},"URL":"https:\/\/doi.org\/10.1093\/oncolo\/oyag317","relation":{},"ISSN":["1083-7159","1549-490X"],"issn-type":[{"value":"1083-7159","type":"print"},{"value":"1549-490X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,9]]},"published":{"date-parts":[[2026,8,6]]},"article-number":"oyag317"}}