CXCR3 expression in regulatory T cells drives interactions with type I dendritic cells in tumors to restrict CD8+ T cell antitumor immunity.

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.

Breaking up the CD8+ T cell: Treg pas de deux.

Checkpoint blockade immunotherapies, such as anti-programmed death-1 (PD-1), unleash anti-tumor CD8+ T cell responses but may also induce immunosuppressive regulatory T cells (Tregs). In this issue of Cancer Cell, Geels et al. uncover that anti-PD-1 leads to Treg expansion via interleukin-2 (IL-2)-producing CD8+ T cells. Combining anti-PD-1 with anti-ICOSL interrupts this crosstalk, thereby enhancing tumor control.