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

• Published in: Science immunology Vol. 8; no. 90; p. eabo5558
• Main Authors: Whiteside, Sarah K, Grant, Francis M, Alvisi, Giorgia, Clarke, James, Tang, Leqi, Imianowski, Charlotte J, Zhang, Baojie, Evans, Alexander C, Wesolowski, Alexander J, Conti, Alberto G, Yang, Jie, Lauder, Sarah N, Clement, Mathew, Humphreys, Ian R, Dooley, James, Burton, Oliver, Liston, Adrian, Alloisio, Marco, Voulaz, Emanuele, Langhorne, Jean, Okkenhaug, Klaus, Lugli, Enrico, Roychoudhuri, Rahul
• Format: Journal Article
• Language: English
• Published: United States 22.12.2023
• Subjects: Animals; Forkhead Transcription Factors - metabolism; Humans; Immunotherapy; Interleukin-10 - metabolism; Mice; Neoplasms - metabolism; Neoplasms - therapy; T-Lymphocytes, Regulatory
• ISSN: 2470-9468
• DOI: 10.1126/sciimmunol.abo5558

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