Siah2 control of T-regulatory cells limits anti-tumor immunity

• Published in: Nature communications 2020-01, Vol.11 (1), p.99-99, Article 99
• Main Authors: Scortegagna, Marzia, Hockemeyer, Kathryn, Dolgalev, Igor, Poźniak, Joanna, Rambow, Florian, Li, Yan, Feng, Yongmei, Tinoco, Roberto, Otero, Dennis C., Zhang, Tongwu, Brown, Kevin, Bosenberg, Marcus, Bradley, Linda M., Marine, Jean-Christophe, Aifantis, Ioannis, Ronai, Ze’ev A.
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/21; 13/31; 13/51; 13/89; 14; 14/63; 38; 38/39; 631/250/2502; 631/67; 631/67/1813; 631/67/580; 631/80; Animals; CCL22 protein; Cell culture; Cell cycle; Chemokine CCL17 - genetics; Chemokine CCL17 - immunology; Chemokine CCL22 - genetics; Chemokine CCL22 - immunology; Cyclin-dependent kinase; Cyclin-dependent kinase inhibitor p27; Cyclin-dependent kinases; Enzyme inhibitors; Forkhead Box Protein O3 - genetics; Forkhead Box Protein O3 - immunology; Foxp3 protein; Human behavior; Humanities and Social Sciences; Humans; Immune system; Immunity; Immunoregulation; Inflammation; Inflammatory response; Kinases; Lymphocytes; Lymphocytes T; Melanoma; Melanoma - genetics; Melanoma - immunology; Metastases; Mice; Mice, Knockout; multidisciplinary; Mutants; Nuclear Proteins - genetics; Nuclear Proteins - immunology; PD-1 protein; Science; Science (multidisciplinary); Substrate inhibition; T-Lymphocytes, Regulatory - immunology; Therapy; Tumors; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - immunology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13826-7

Understanding the mechanisms underlying anti-tumor immunity is pivotal for improving immune-based cancer therapies. Here, we report that growth of BRAF-mutant melanoma cells is inhibited, up to complete rejection, in Siah2 −/− mice. Growth-inhibited tumors exhibit increased numbers of intra-tumoral activated T cells and decreased expression of Ccl17, Ccl22 , and Foxp3 . Marked reduction in Treg proliferation and tumor infiltration coincide with G1 arrest in tumor infiltrated Siah2 −/− Tregs in vivo or following T cell stimulation in culture, attributed to elevated expression of the cyclin-dependent kinase inhibitor p27, a Siah2 substrate. Growth of anti-PD-1 therapy resistant melanoma is effectively inhibited in Siah2 −/− mice subjected to PD-1 blockade, indicating synergy between PD-1 blockade and Siah2 loss. Low SIAH2 and FOXP3 expression is identified in immune responsive human melanoma tumors. Overall, Siah2 regulation of Treg recruitment and cell cycle progression effectively controls melanoma development and Siah2 loss in the host sensitizes melanoma to anti-PD-1 therapy. The ubiquitin ligase Siah2 has been implicated in immune responses. Here, the authors show that Siah2 null immune cells have an increased inflammatory response to inoculated melanoma cells, along with a reduced number of infiltrating immunosuppressive regulatory T cells, resulting in inhibition of tumour growth.