DOI: 10.1126/sciimmunol.abo5558 ISSN: 2470-9468

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

Sarah K. Whiteside, Francis M. Grant, Giorgia Alvisi, James Clarke, Leqi Tang, Charlotte J. Imianowski, Baojie Zhang, Alexander C. Evans, Alexander J. Wesolowski, Alberto G. Conti, Jie Yang, Sarah N. Lauder, Mathew Clement, Ian R. Humphreys, James Dooley, Oliver Burton, Adrian Liston, Marco Alloisio, Emanuele Voulaz, Jean Langhorne, Klaus Okkenhaug, Enrico Lugli, Rahul Roychoudhuri
  • General Medicine
  • Immunology

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.

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