Siah2 control on tumor environment

Understanding mechanisms underlying anti-tumor immunity is pivotal for improving immune-based cancer therapies. Here we demonstrate that growth of inoculated BRAF mutant melanoma cells was inhibited in Siah2-/- mice, up to a complete loss. Melanoma grown in Siah2-/- mice exhibited increased proinflammatory immune components, signified by enhanced intra-tumoral activated T cells, along with decreased expression of Ccl17 and Ccl22, and decreased Foxp3 expression. A marked reduction in Treg proliferation was associated with inhibition of Treg cell cycle progression. Correspondingly, G1 cell cycle arrest in Siah2-/- Tregs coincided with elevated expression of the cyclin dependent kinase inhibitor p27, a Siah2 substrate. Growth of PD1-unresponsive melanoma was effectively inhibited up to complete tumor rejection in Siah2-/- mice subjected to PD1 blockade, highlighting synergy between PD1 inhibition and Siah2 loss. Siah2 regulation of Treg recruitment and cell cycle progression effectively controls melanoma development and confers synthetic lethality when combined with anti-PD1 therapy. 5 melanoma tumors grown in WT mice and 5 melanoma tumors grown in siah2 knock out mice were analyzed