Acquisition of suppressive function by conventional T cells limits antitumor immunity upon Treg depletion

Abstract

Regulatory T (T_reg) cells contribute to immune homeostasis but suppress immune responses to cancer. Strategies to disrupt T_reg cell-mediated cancer immunosuppression have been met with limited clinical success, but the underlying mechanisms for treatment failure are poorly understood. By modeling T_reg cell-targeted immunotherapy in mice, we find that CD4⁺ Foxp3^- conventional T (T_conv) cells acquire suppressive function upon depletion of Foxp3⁺ T_reg cells, limiting therapeutic efficacy. Foxp3^- T_conv cells within tumors adopt a T_reg cell-like transcriptional profile upon ablation of T_reg cells and acquire the ability to suppress T cell activation and proliferation ex vivo. Suppressive activity is enriched among CD4⁺ T_conv cells marked by expression of C-C motif receptor 8 (CCR8), which are found in mouse and human tumors. Upon T_reg cell depletion, CCR8⁺ T_conv cells undergo systemic and intratumoral activation and expansion, and mediate IL-10-dependent suppression of antitumor immunity. Consequently, conditional deletion of Il10 within T cells augments antitumor immunity upon T_reg cell depletion in mice, and antibody blockade of IL-10 signaling synergizes with T_reg cell depletion to overcome treatment resistance. These findings reveal a secondary layer of immunosuppression by T_conv cells released upon therapeutic T_reg cell depletion and suggest that broader consideration of suppressive function within the T cell lineage is required for development of effective T_reg cell-targeted therapies.