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Coprimary endpoints included 6-month complete metabolic response rate (94%) and 2-year progression-free survival (84%). Induction yielded a 46% major histopathologic response rate. Single-cell profiling revealed responders had higher baseline intratumoral CD8+ T cells with a tumor-reactive, tissue-resident memory (TRM) phenotype and a treatment-related decrease in effector regulatory T (eTreg) cells. The eTreg decrease correlated with CD8+ T-cell clonotype transitioning from TRM to effector memory and IFNG+ effector cells. In nonresponders, clonotypes transitioned to exhausted TRM and proliferating cells. Multivariable regression modeling determined that the baseline feature most associated with reduction in tumor viability was the proportion of FCGR3A-expressing NK cells, which are capable of ipilimumab-dependent depletion of CTLA4high eTregs. eTreg depletion may be critical for major response to induction dual immune checkpoint blockade (ICB).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>The relative contributions of CD28 costimulation restoration versus Treg depletion to clinical response to CTLA4 ICB is a matter of considerable controversy. In this study, we provide compelling data that eTreg depletion is critical to tumor clearance in patients treated with dual PD-1 and CTLA4 ICB.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-1390","type":"journal-article","created":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T08:22:24Z","timestamp":1744964544000},"page":"1569-1592","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Depletion of Effector Regulatory T Cells Associates with Major Response to Induction Dual Immune Checkpoint Blockade"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1697-8575","authenticated-orcid":false,"given":"Xianli","family":"Jiang","sequence":"first","affiliation":[{"name":"1Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9720-3124","authenticated-orcid":false,"given":"Nils-Petter","family":"Rudqvist","sequence":"additional","affiliation":[{"name":"2Department of Thoracic Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8341-1750","authenticated-orcid":false,"given":"Bo","family":"Jiang","sequence":"additional","affiliation":[{"name":"2Department of Thoracic Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8767-2595","authenticated-orcid":false,"given":"Shengbin","family":"Ye","sequence":"additional","affiliation":[{"name":"1Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer 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