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

Nat Commun. 2020 Jan 7;11(1):99. 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Chemokine CCL17 / genetics
  • Chemokine CCL17 / immunology
  • Chemokine CCL22 / genetics
  • Chemokine CCL22 / immunology
  • Forkhead Box Protein O3 / genetics
  • Forkhead Box Protein O3 / immunology
  • Humans
  • Melanoma / genetics
  • Melanoma / immunology*
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Nuclear Proteins / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / immunology*


  • Chemokine CCL17
  • Chemokine CCL22
  • Forkhead Box Protein O3
  • Nuclear Proteins
  • Siah2 protein, mouse
  • Ubiquitin-Protein Ligases
  • seven in absentia proteins