SOCS1 is a crucial regulator for uveal melanoma response to immunotherapy PROJECT SUMMARY/ABSTRACT Targeted and immune therapies generated remarkable clinical responses in cutaneous melanoma (CM) patients. However, uveal melanoma (UM) is among those cancer types that have benefited little or not at all from targeted therapy or immune checkpoint inhibitors (CPIs). Currently, there is no FDA-approved systemic therapy for patients with metastatic UM. The mechanism underlying poor response to CPIs in UM is unclear. There is an urgent need to develop effective prognostic markers and immunotherapies for UM patients. To characterize the immunosuppressive mechanisms in UM, we initiated a study of immune profiling UM tumors derived from patients treated with CPIs. Our preliminary data showed that the suppressor of cytokine signaling 1 (SOCS1) was significantly higher in pre-treatment tumors of responders than nonresponders. Moreover, SOCS1 is correlated with UM patients′ survival and most major histocompatibility complex (MHC) molecules′ expressions. SOCS1 is a known prominent regulator of cytokine signaling and tumor microenvironment. To date, a major gap lies in our understanding of the functional role of SOCS1 in UM. Herein, we hypothesize that SOCS1 is a crucial factor regulating the immune infiltrates and tumor immunogenicity of UM via promoting MHC molecules’ expression. Markedly, the suppression of SOCS1 underlies the poor response to immune CPIs in UM, and upregulation of SOCS1 in tumors can overcome this drug resistance. Thus, we propose the following specific aims of preclinical translational research to investigate the role of SOCS1 in immune-silent UM tumors. Aim 1) To characterize the SOCS1-associated immune signature of UM that correlates with the patient's clinical response to immune CPIs. Aim 2) To investigate the epigenetic and transcriptional mechanisms suppressing SOCS1 and MHC expressions in immune cold UM cells. Aim 3) To enhance the immune response in UM tumors by SOCS1 modulators and further examine their antitumor effects in combination with CPIs. In this project, the levels and function of various immune infiltrates related to SOCS1 will be profiled in UM tumors. We will identify a distinct SOCS1-associated immune signature that can be a predictive marker for UM patient’s response to CPIs and overall survival. Moreover, by unveiling the signaling pathways or factors suppressing SOCS1 and MHC expressions in UM, we expect to identify novel drug targets to upregulate the expressions of these genes, which will convert an immune cold into a hot tumor. For the first time, we will investigate a novel strategy to combine small modulators that can upregulate SOCS1 expression with CPIs to enhance the anticancer immunity of cytotoxic T cells against UM tumors. The proposed studies are expected to produce data to address one unmet need for developing effective targeted and immune therapies for UM. This project has great translational potentia...