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

Marzia Scortegagna1, Kathryn Hockemeyer2, Igor Dolgalev2

  • 1Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA. mscortegagna@sbpdiscovery.org.

Nature Communications
|January 9, 2020
PubMed

Insights

Loss of Siah2 protein inhibits BRAF-mutant melanoma growth by enhancing anti-tumor immunity and Treg cell cycle arrest. Siah2 deficiency also sensitizes melanoma to anti-PD-1 therapy.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Anti-tumor immunity is crucial for effective cancer therapies.
  • BRAF-mutant melanoma poses a significant therapeutic challenge.
  • Regulatory T cells (Tregs) play a complex role in tumor immune evasion.

Purpose of the Study:

  • To investigate the role of Siah2 in anti-tumor immunity and melanoma development.
  • To explore the impact of Siah2 deficiency on Treg cells and melanoma growth.
  • To assess the therapeutic potential of targeting Siah2 in combination with PD-1 blockade.

Main Methods:

  • Utilized Siah2 knockout (Siah2-/-) mouse models with BRAF-mutant melanoma.
  • Analyzed tumor immune cell infiltration, cytokine expression (Ccl17, Ccl22), and Treg markers (Foxp3).
  • Assessed Treg proliferation, cell cycle progression (G1 arrest), and p27 expression in vitro and in vivo.
  • Evaluated the efficacy of anti-PD-1 therapy in Siah2-/- mice with resistant melanoma.

Main Results:

  • Siah2-/- mice exhibited significant inhibition and rejection of BRAF-mutant melanoma.
  • Tumors in Siah2-/- mice showed increased activated T cells and reduced Treg infiltration and proliferation.
  • Siah2 deficiency led to G1 arrest in Tregs, associated with elevated p27 expression.
  • Combined Siah2 loss and anti-PD-1 blockade effectively inhibited therapy-resistant melanoma growth.
  • Low SIAH2 and FOXP3 expression correlated with immune-responsive human melanoma.

Conclusions:

  • Siah2 regulates Treg recruitment and cell cycle progression, controlling melanoma development.
  • Host Siah2 deficiency enhances anti-tumor immunity and sensitizes melanoma to anti-PD-1 therapy.
  • Targeting Siah2 represents a potential strategy to improve melanoma immunotherapy outcomes.

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