CXCR3 expression in regulatory T cells drives interactions with type I dendritic cells in tumors to restrict CD8+ T cell antitumor immunity
- PMID: 37392735
- PMCID: PMC10752240
- DOI: 10.1016/j.immuni.2023.06.003
CXCR3 expression in regulatory T cells drives interactions with type I dendritic cells in tumors to restrict CD8+ T cell antitumor immunity
Abstract
Infiltration of regulatory T (Treg) cells, an immunosuppressive population of CD4+ T cells, into solid cancers represents a barrier to cancer immunotherapy. Chemokine receptors are critical for Treg cell recruitment and cell-cell interactions in inflamed tissues, including cancer, and thus are an ideal therapeutic target. Here, we show in multiple cancer models that CXCR3+ Treg cells were increased in tumors compared with lymphoid tissues, exhibited an activated phenotype, and interacted preferentially with CXCL9-producing BATF3+ dendritic cells (DCs). Genetic ablation of CXCR3 in Treg cells disrupted DC1-Treg cell interactions and concomitantly increased DC-CD8+ T cell interactions. Mechanistically, CXCR3 ablation in Treg cells increased tumor antigen-specific cross-presentation by DC1s, increasing CD8+ T cell priming and reactivation in tumors. This ultimately impaired tumor progression, especially in combination with anti-PD-1 checkpoint blockade immunotherapy. Overall, CXCR3 is shown to be a critical chemokine receptor for Treg cell accumulation and immune suppression in tumors.
Keywords: CXCR3; Tregs; cancer; checkpoint blockade; cross presentation; dendritic cells; immunotherapy; regulatory T cells.
Copyright © 2023 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests M.A.M.A. is currently employed by Revolution Medicines (Redwood City, CA).
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Comment in
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Th1-like Treg cells are dressed to suppress anti-tumor immunity.Immunity. 2023 Jul 11;56(7):1437-1439. doi: 10.1016/j.immuni.2023.06.014. Immunity. 2023. PMID: 37437535 Free PMC article.
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Of tenants and nomads: The faces of memory T cells.Immunity. 2023 Jul 11;56(7):1439-1442. doi: 10.1016/j.immuni.2023.06.011. Immunity. 2023. PMID: 37437536
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