S1PR1 Is Crucial for Accumulation of Regulatory T Cells in Tumors via STAT3

• S1PR1 regulates tumor accumulation of Tregs while restraining them in the periphery
• S1PR1-mediated Treg accumulation limits CD8+ T cell recruitment and activation in tumors
• S1PR1 signaling in CD4+, but not CD8+, T cells promotes tumor growth
• S1PR1-mediated tumor accumulation of Treg cells requires JAK/STAT3 signaling

SummaryS1PR1 signaling has been shown to restrain the number and function of regulatory T (Treg) cells in the periphery under physiological conditions and in colitis models, but its role in regulating tumor-associated T cells is unknown. Here, we show that S1PR1 signaling in T cells drives Treg accumulation in tumors, limits CD8+ T cell recruitment and activation, and promotes tumor growth. T-cell-intrinsic S1PR1 affects Treg cells, but not CD8+ T cells, as demonstrated by adoptive transfer models and transient pharmacological S1PR1 modulation. An increase in S1PR1 in CD4+ T cells promotes STAT3 activation and JAK/STAT3-dependent Treg tumor migration, whereas STAT3 ablation in T cells diminishes tumor-associated Treg accumulation and tumor growth. Our study demonstrates a stark contrast between the consequences of S1PR1 signaling in Treg cells in the periphery versus tumors.

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