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Acquisition of suppressive function by conventional T cells limits antitumor immunity upon Treg depletion.
- Source :
- Science Immunology; 2023, Vol. 8 Issue 90, p1-16, 16p
- Publication Year :
- 2023
-
Abstract
- Regulatory T (T<subscript>reg</subscript>) cells contribute to immune homeostasis but suppress immune responses to cancer. Strategies to disrupt T<subscript>reg</subscript> cell–mediated cancer immunosuppression have been met with limited clinical success, but the underlying mechanisms for treatment failure are poorly understood. By modeling T<subscript>reg</subscript> cell–targeted immunotherapy in mice, we find that CD4<superscript>+</superscript> Foxp3<superscript>−</superscript> conventional T (T<subscript>conv</subscript>) cells acquire suppressive function upon depletion of Foxp3<superscript>+</superscript> T<subscript>reg</subscript> cells, limiting therapeutic efficacy. Foxp3<superscript>−</superscript> T<subscript>conv</subscript> cells within tumors adopt a T<subscript>reg</subscript> cell–like transcriptional profile upon ablation of T<subscript>reg</subscript> cells and acquire the ability to suppress T cell activation and proliferation ex vivo. Suppressive activity is enriched among CD4<superscript>+</superscript> T<subscript>conv</subscript> cells marked by expression of C-C motif receptor 8 (CCR8), which are found in mouse and human tumors. Upon T<subscript>reg</subscript> cell depletion, CCR8<superscript>+</superscript> T<subscript>conv</subscript> 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<subscript>reg</subscript> cell depletion in mice, and antibody blockade of IL-10 signaling synergizes with T<subscript>reg</subscript> cell depletion to overcome treatment resistance. These findings reveal a secondary layer of immunosuppression by T<subscript>conv</subscript> cells released upon therapeutic T<subscript>reg</subscript> cell depletion and suggest that broader consideration of suppressive function within the T cell lineage is required for development of effective T<subscript>reg</subscript> cell–targeted therapies. Editor's Summary: Regulatory T (T<subscript>reg</subscript>) cells have immunosuppressive properties, which has led to the development of T<subscript>reg</subscript> cell–depleting cancer immunotherapies. Targeted T<subscript>reg</subscript> cell depletion has had limited clinical efficacy, and Whiteside et al. examined the underlying mechanism of treatment failure using a mouse model of T<subscript>reg</subscript> cell–targeted immunotherapy. Upon T<subscript>reg</subscript> cell depletion, intratumoral CD4<superscript>+</superscript> Foxp3<superscript>−</superscript> conventional T (T<subscript>conv</subscript>) cells acquired T<subscript>reg</subscript> cell transcriptional characteristics and assumed immunosuppressive properties as measured ex vivo. Depletion of T<subscript>reg</subscript> cells caused expansion of CCR8-expressing T<subscript>conv</subscript> cells, which drove IL-10–mediated suppression of antitumor immunity. Consequently, resistance to T<subscript>reg</subscript> 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]
Details
- Language :
- English
- ISSN :
- 24709468
- Volume :
- 8
- Issue :
- 90
- Database :
- Complementary Index
- Journal :
- Science Immunology
- Publication Type :
- Academic Journal
- Accession number :
- 174638412
- Full Text :
- https://doi.org/10.1126/sciimmunol.abo5558