{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T19:24:37Z","timestamp":1793733877529,"version":"4.6.1"},"reference-count":50,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2024,1,1]],"date-time":"2024-01-01T00:00:00Z","timestamp":1704067200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"RK is funded","award":["5U01CA180888-08"],"award-info":[{"award-number":["5U01CA180888-08"]}]},{"name":"RK is funded","award":["5UG1CA233198-05"],"award-info":[{"award-number":["5UG1CA233198-05"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Ther Adv Med Oncol"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>CTLA-4 impedes the immune system\u2019s antitumor response. There are two Food and Drug Administration-approved anti-CTLA-4 agents \u2013 ipilimumab and tremelimumab \u2013 both used together with anti-PD-1\/PD-L1 agents.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>To assess the prognostic implications and immunologic correlates of high CTLA-4 in tumors of patients on immunotherapy and those on non-immunotherapy treatments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design\/methods:<\/jats:title>\n                    <jats:p>We evaluated RNA expression levels in a clinical-grade laboratory and clinical correlates of CTLA-4 and other immune checkpoints in 514 tumors, including 489 patients with advanced\/metastatic cancers and full outcome annotation. A reference population (735 tumors; 35 histologies) was used to normalize and rank transcript abundance (0\u2013100 percentile) to internal housekeeping gene profiles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>The most common tumor types were colorectal (140\/514, 27%), pancreatic (55\/514, 11%), breast (49\/514, 10%), and ovarian cancers (43\/514, 8%). Overall, 87 of 514 tumors (16.9%) had high CTLA-4 transcript expression (\u2a7e75th percentile rank). Cancers with the largest proportion of high CTLA-4 transcripts were cervical cancer (80% of patients), small intestine cancer (33.3%), and melanoma (33.3%). High CTLA-4 RNA independently\/significantly correlated with high PD-1, PD- L2, and LAG3 RNA levels (and with high PD-L1 in univariate analysis). High CTLA-4 RNA expression was not correlated with survival from the time of metastatic disease [ N\u2009=\u2009272 patients who never received immune checkpoint inhibitors (ICIs)]. However, in 217 patients treated with ICIs (mostly anti-PD-1\/anti-PD- L1), progression-free survival (PFS) and overall survival (OS) were significantly longer among patients with high versus non-high CTLA-4 expression [hazard ratio, 95% confidence interval: 0.6 (0.4\u20130.9) p\u2009=\u20090.008; and 0.5 (0.3\u20130.8) p\u2009=\u20090.002, respectively]; results were unchanged when 18 patients who received anti-CTLA-4 were omitted. Patients whose tumors had high CTLA-4 and high PD-L1 did best; those with high PD-L1 but non-high CTLA-4 and\/or other expression patterns had poorer outcomes for PFS ( p\u2009=\u20090.004) and OS ( p\u2009=\u20090.009) after immunotherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>High CTLA-4, especially when combined with high PD-L1 transcript expression, was a significant positive predictive biomarker for better outcomes (PFS and OS) in patients on immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/17588359231220510","type":"journal-article","created":{"date-parts":[[2024,1,6]],"date-time":"2024-01-06T03:57:57Z","timestamp":1704513477000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":27,"title":["High CTLA-4 transcriptomic expression correlates with high expression of other checkpoints and with immunotherapy outcome"],"prefix":"10.1177","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9091-1927","authenticated-orcid":false,"given":"Nithya","family":"Krishnamurthy","sequence":"first","affiliation":[{"name":"Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029-6574, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Nishizaki","sequence":"additional","affiliation":[{"name":"Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott M.","family":"Lippman","sequence":"additional","affiliation":[{"name":"Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotaka","family":"Miyashita","sequence":"additional","affiliation":[{"name":"Dartmouth Cancer Center, Hematology and Medical Oncology, Lebanon, NH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary K.","family":"Nesline","sequence":"additional","affiliation":[{"name":"OmniSeq Inc. (Labcorp), Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarabjot","family":"Pabla","sequence":"additional","affiliation":[{"name":"OmniSeq Inc. (Labcorp), Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Conroy","sequence":"additional","affiliation":[{"name":"OmniSeq Inc. (Labcorp), Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"DePietro","sequence":"additional","affiliation":[{"name":"OmniSeq Inc. 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