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

Marzia Scortegagna,Ze’Ev A Ronai,Linda M Bradley,Florian Rambow,Kevin Brown,Yongmei Feng,Roberto Tinoco,Marcus Bosenberg,Yan Li,Dennis C Otero,Igor Dolgalev,Joanna Poźniak,Kathryn Hockemeyer,Tongwu Zhang,Ioannis Aifantis,Jean-Christophe Marine

doi:10.1038/s41467-019-13826-7

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.

Highlights

Understanding the mechanisms underlying anti-tumor immunity is pivotal for improving immune-based cancer therapies
Here, we identify a role for the ubiquitin ligase Siah[2] in control of intratumoral T regulatory cells (Tregs) proliferation and tumor infiltration
Relative to WT mice, Siah2−/− mice inoculated with YUMMER1.7 melanoma cells showed a decreased number of Tregs within tumors as well as inhibited tumor growth, up to complete regression

Summary

Introduction

Understanding the mechanisms underlying anti-tumor immunity is pivotal for improving immune-based cancer therapies. The E3 ubiquitin ligase Siah[2] functions to control a number of fundamental cellular processes, including hypoxia[17,18], the unfolded protein response (UPR19), cell junction integrity[20], mitochondrial dynamics[21], intracellular signaling[22], cellular metabolism[23], and cell proliferation[24,25,26,27]. While these activities are associated with immune cell function, direct evidence for Siah[2] regulation of anti-tumor immunity has been lacking. We demonstrate that via its regulation of p27 stability in stimulated T cells, Siah[2] controls T cell proliferation, which affects the availability of intratumoral Treg, but not effector T cells, thereby enhancing effectiveness of the cytotoxic T cell and overall anti-tumor immunity

Methods

Results

Conclusion