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

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. Editor's Summary: Regulatory T (T_reg) cells have immunosuppressive properties, which has led to the development of T_reg cell–depleting cancer immunotherapies. Targeted T_reg cell depletion has had limited clinical efficacy, and Whiteside et al. examined the underlying mechanism of treatment failure using a mouse model of T_reg cell–targeted immunotherapy. Upon T_reg cell depletion, intratumoral CD4⁺ Foxp3⁻ conventional T (T_conv) cells acquired T_reg cell transcriptional characteristics and assumed immunosuppressive properties as measured ex vivo. Depletion of T_reg cells caused expansion of CCR8-expressing T_conv cells, which drove IL-10–mediated suppression of antitumor immunity. Consequently, resistance to T_reg cell depletion could be prevented through conditional deletion of Il10 in T cells or cotreatment with antibodies that block IL-10 signaling. These findings highlight multiple layers of immunosuppression that can be overcome to unleash cancer immunotherapy efficacy. —Christiana Fogg [ABSTRACT FROM AUTHOR]