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Immune checkpoint blockade has shown clinical activity in a range of cancer types. To dissect the effect of neoadjuvant PD-1 and CTLA4 blockade on intratumoral T cells in head and neck squamous cell carcinoma, we analyzed immune infiltrates in tumor biopsies from responding and non-responding patients. At baseline, a higher ratio between active (4-1BB+) and inactive regulatory CD4+ T cells was associated with response to therapy. Furthermore, upon therapy, this active Treg population showed a profound decrease in responding patients. In an analogous process, intratumoral dysfunctional CD8+ T cells transitioned to a state of reduced activity and dysfunction in responding patients, while in non-responding patients, NK cells showed an increased cytotoxic transcriptional profile upon treatment. These data reveal the immunological changes in response to dual PD-1 and CTLA4 blockade, including a parallel remodeling of presumed tumor-reactive T cell compartments in responding patients, and indicate that the presence of an activated Treg compartment at baseline may predict response. Citation Format: Anne M. van der Leun, Joleen J. Traets, Joris L. Vos, Joris B. Elbers, Sanne Patiwael, Xiaohang Qiao, Mercedes Machuca-Ostos, Daniela S. Thommen, John B. Haanen, Ton N. Schumacher, Charlotte L. Zuur. Dual immune checkpoint blockade induces analogous alterations in the dysfunctional CD8+ T cell and activated Treg compartment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2281.