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

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 ORCID: https://orcid.org/0000-0002-9280-5281, Humphreys, Ian R. ORCID: https://orcid.org/0000-0002-9512-5337, Dooley, James, Burton, Oliver, Liston, Adrian, Alloisio, Marco, Voulaz, Emanuele, Langhorne, Jean, Okkenhaug, Klaus, Lugli, Enrico and Roychoudhuri, Rahul 2023. Acquisition of suppressive function by conventional T cells limits antitumor immunity upon Treg depletion. Science Immunology 8 (90) , eabo5558. 10.1126/sciimmunol.abo5558

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Abstract

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

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Association for the Advancement of Science
ISSN:	2470-9468
Date of First Compliant Deposit:	19 December 2023
Date of Acceptance:	10 November 2023
Last Modified:	13 Nov 2024 03:45
URI:	https://orca.cardiff.ac.uk/id/eprint/164889

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