Depletion of effector regulatory T cells drives major response to induction dual immune checkpoint blockade

In a phase 2 trial, local-regionally advanced HPV-positive oropharyngeal carcinoma (OPC) patients received ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) as induction immunotherapy and concurrently with radiotherapy ([NCT03799445][1]). Co-primary endpoints achieved included 6-month complete metabolic response rate (94%) and 2-year progression-free survival (84%). Induction yielded a 46% major histological response rate. Single-cell profiling revealed responders had higher baseline intratumoral tissue-resident memory (TRM) CD8+ T cells and NK cells expressing Fc Gamma Receptor IIIa ( FCGR3A ). Decreases in effector regulatory T (eTreg) cells, which highly expressed CTLA4 , occurred only in responders, suggesting ipilimumab-dependent depletion by FCGR3A+ NK cells. eTreg depletion correlated with increased Interferon Gamma ( IFNG )+ effector CD8+ T cells. CD8+ T-cell clonotypes transitioned from TRM to effector memory and IFNG+ effector cells in responders, whereas clonotypes transitioned to exhausted TRM and proliferating cells in nonresponders. We conclude that eTreg depletion is critical for major response to induction dual immune checkpoint blockade. ### Competing Interest Statement M.L.G. has consulted for LLX Solutions, LLC, Sensei, Mirati Therapeutics, BioNTech AG, Shattuck Labs Inc., EMD Serono Inc., Debiopharm, Kura Oncology, Merck Co., Ipsen Biopharmaceuticals Inc., Bristol-Myers Squibb, Bicara Therapeutics, Bayer HealthCare Pharmaceuticals, Roche, Roche Diagnostics GmbH, Genocea Biosciences, Inc., NewLink Genetics Corporation, Aspyrian Therapeutics, TRM Oncology, Amgen Inc., AstraZeneca Pharmaceuticals, and Celgene Corp.; and research funding from Genocea, BMS, Kura, Cullinan, Genentech, BioNtech, and Gilead. ### Clinical Trial NCT03799445 ### Funding Statement The clinical trial was supported by Bristol Myers Squibb. All correlative data were supported by grants to M.L.G. from CPRIT, the Oral Cancer Foundation, and The MD Anderson HPV-related Cancers Moonshot Program; to X.J. from CPRIT (RP170593); and to K.C. from the NIH (U01CA247760). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The institutional review board of The University of Texas MD Anderson Cancer Center gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [ClinicalTrials.gov][2]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03799445&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F04%2F2024.01.04.23300616.atom [2]: http://ClinicalTrials.gov