Inducible Regulatory T Cell Predicts Efficacy of PD‐1 Blockade Therapy in Melanoma

Metastatic melanoma is a lethal disease with poor prognosis. Here, a patient is being studied with metastatic uveal melanoma whose liver metastases have heterogeneous response to PD-1 inhibitor. The progressive disease (PD) lesion is found to have more than two times the abundance of inducible regulatory T cell (iTreg) compared with the complete response (CR) lesion. Based on public datasets, high abundance of pretreatment iTreg is found able to predict poor response to PD-1 inhibitor and is correlated with unfavorable prognosis of patients with advanced cutaneous melanoma receiving PD-1 blockade therapy. Further, based on single-cell RNA sequencing data, the ratio of iTregs to CD8(+)T cells is found significantly increased from pretreatment to post-treatment status in nonresponders, while no such changes are found among responders. In nonresponders, iTreg cells have increased expression of IL-10 and maintained high expression of PRDM1. The top enriched pathway in iTregs includes Il6-Jak-Stat3 Signaling, Il2-Stat5 Signaling, and Glycolysis. A series of targeted or small molecule drugs predicted by iTreg specific genes are introduced. This study provides an insight into the immune suppressive role of iTreg in immunotherapy for melanoma.