1. CXCR3 expression in regulatory T cells drives interactions with type I dendritic cells in tumors to restrict CD8+ T cell antitumor immunity.
- Author
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Moreno Ayala, Mariela, Campbell, Timothy, Zhang, Chenyu, Dahan, Noa, Bockman, Alissa, Prakash, Varsha, Feng, Lawrence, Sher, Theo, and DuPage, Michel
- Subjects
CXCR3 ,Tregs ,cancer ,checkpoint blockade ,cross presentation ,dendritic cells ,immunotherapy ,regulatory T cells ,Humans ,T-Lymphocytes ,Regulatory ,Neoplasms ,CD8-Positive T-Lymphocytes ,Immunotherapy ,Dendritic Cells ,Receptors ,CXCR3 - 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.
- Published
- 2023