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

Marzia Scortegagna (), Kathryn Hockemeyer, Igor Dolgalev, Joanna Poźniak, Florian Rambow, Yan Li, Yongmei Feng, Roberto Tinoco, Dennis C. Otero, Tongwu Zhang, Kevin Brown, Marcus Bosenberg, Linda M. Bradley, Jean-Christophe Marine, Ioannis Aifantis () and Ze’ev A. Ronai ()
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Marzia Scortegagna: Sanford Burnham Prebys Medical Discovery Institute
Kathryn Hockemeyer: NYU School of Medicine
Igor Dolgalev: NYU School of Medicine
Joanna Poźniak: KU Leuven Oncology Department
Florian Rambow: KU Leuven Oncology Department
Yongmei Feng: Sanford Burnham Prebys Medical Discovery Institute
Roberto Tinoco: Sanford Burnham Prebys Medical Discovery Institute
Dennis C. Otero: Sanford Burnham Prebys Medical Discovery Institute
Tongwu Zhang: National Cancer Institute
Kevin Brown: National Cancer Institute
Marcus Bosenberg: Yale University, School of Medicine
Linda M. Bradley: Sanford Burnham Prebys Medical Discovery Institute
Jean-Christophe Marine: KU Leuven Oncology Department
Ioannis Aifantis: NYU School of Medicine
Ze’ev A. Ronai: Sanford Burnham Prebys Medical Discovery Institute

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-019-13826-7

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