Abstract A147: Sunitinib upregulates IFNγ-STAT1 signaling to modulate the tumor immune microenvironment in renal cell carcinoma

Abstract

Abstract Antiangiogenic therapy is the current mainstay of treatment for renal cell carcinoma (RCC). Recently we reported that antiangiogenic therapy-treated primary tumors demonstrated both increased infiltration of CD4 and CD8 T cells and higher expression of the immune checkpoint ligand PD-L1, all of which were associated with therapy resistance. The underlying mechanism remains unknown. IFNγ-STAT1 signaling pathway drives the expression of both immunosuppressive PD-L1, and immunostimulatory chemoattractants, adhesion molecules and class I antigen presentation components. We studied the effects of sunitinib on the IFNγ-STAT1 signaling pathway. We found that sunitinib treatment magnified IFNγ-induced STAT1 activity. Sunitinib not only increased the activity of janus kinase (JAK) and the tyrosine phosphorylation of STAT1, but also decreased the protein level of PIAS and SOCS, negative regulators of STAT1 signaling. These results indicate that sunitinib treatment potently activates IFNγ-mediated STAT1 signaling by modulating both activators and inhibitors of STAT1. Further investigation is underway into the precise signaling pathways involved in sunitinib mediated regulation of upstream regulators of STAT1, and on the effect of sunitinib mediated STAT1 signaling on other immunostimulatory molecules in the tumor cell. Understanding the impact of STAT1 activation on target proteins after stimulation by antiangiogenic therapy will guide us to develop predictive biomarkers for combination antiangiogenic and immunomodulatory therapy, and devise precise interventions to overcome tumor cell specific immunosuppressive signaling. Citation Format: Xian-De Liu, Anh Hoang, Mianen Sun, Zhou Lijun, Zhiyong Ding, Xuesong Zhang, Shanshan Bai, Nizar Tannir, Eric Jonasch. Sunitinib upregulates IFNγ-STAT1 signaling to modulate the tumor immune microenvironment in renal cell carcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A147.