Precise Spatiotemporal Interruption of Regulatory T-cell-Mediated CD8⁺ T-cell Suppression Leads to Tumor Immunity

Tumors can develop despite the presence of competent host immunity via a complex system of immune evasion. One of the most studied factors originating from the host is immune suppression by regulatory T cells (Treg). Ample laboratory and clinical evidence suggests that Treg ablation leads to robust antitumor immune activation. However, how Tregs specifically achieve their suppression in the context of tumor progression is not entirely clear, particularly with regard to the timing and location where Treg inhibition takes place. In this work, we report that Tregs migrate to tumor-draining lymph nodes (TDLN) and block expression of sphingosine-1-phosphate receptor 1 (S1P1) on CD8⁺ T cells. This event trapped the CD8⁺ T cells in the TDLN and served as a facilitating factor for tumor growth. Intriguingly, minimalistic depletion of Tregs in TDLN in a short window following tumor inoculation was sufficient to restore CD8⁺ T-cell activities, which resulted in significant tumor reduction. Similar treatments outside this time frame had no such effect. Our work therefore reveals a subtle feature in tumor biology whereby Tregs appear to be driven by newly established tumors for a programmed encounter with newly activated CD8⁺ T cells in TDLN. Our results suggest the possibility that clinical interception of this step can be tested as a new strategy of cancer therapy, with expected high efficacy and low systemic side effects. SIGNIFICANCE: These findings reveal a strong tumor suppressive effect invoked by minimal blockade of tumor draining lymph node regulatory T cells during early versus late tumorigenesis.