Dual immune checkpoint blockade induces analogous alterations in the dysfunctional CD8+ T cell and activated Treg compartment.

To dissect the effect of neoadjuvant PD-1 and CTLA4 blockade on intratumoral T cells in treatment-naive head and neck squamous cell carcinoma, we analyzed primary tumor immune infiltrates from responding and non-responding patients. At baseline, a higher ratio between active (4-1BB/OX-40+) and inactive regulatory CD4+ T cells was associated with immunotherapy response. Furthermore, upon therapy, this active Treg population showed a profound decrease in responding patients. In an analogous process, intratumoral dysfunctional CD8+ T cells displayed decreased expression of activity and dysfunction-related genes in responding patients, while in clinical non-responders NK cells showed an increased cytotoxic profile early upon treatment. These data reveal immunological changes in response to dual PD-1/CTLA4 blockade, including a parallel remodeling of presumed tumor-reactive Treg and CD8+ T cell compartments in responding patients, and indicate that the presence of activated Tregs at baseline may be associated with response.