Dissecting the Sox2-orchestrated transcriptional network that governs immune resistance in tumor initiating cells

PROJECT SUMMARY The treatments for various squamous cell carcinomas (SCCs), such as SCCs of the head and neck, have been revolutionized by the development of immunotherapies. However, even though many treated patients can evoke robust initial responses, most SCC patients often experience rapid tumor relapse, the nature of which is still poorly understood. Such hurdles highlight the dire need to uncover novel mechanisms driving immunotherapy resistance. Understanding tumor relapse after immunotherapy will be vital for advancing clinical outcomes. Thus, the broad research objective of this proposal is to understand the molecular network driving tumor relapse from cancer immunotherapy. Cancer immune evasion is a highly complex process mediated by both an immune suppressive microenvironment and cancer cell-intrinsic resistance mechanisms. Recently, in a genetically engineered mouse model of SCC, we revealed a group of TGFβ-responding tumor- initiating cells (TICs) that hijack many molecular features of adult tissue stem cells. Importantly, these cells appear to be the root of tumor relapse after immunotherapy treatment and are endowed with unique programs that facilitate their remarkable immune resistance. This key finding raised the importance of identifying the critical molecular features for these TICs in driving immune resistance in SCCs. In this study, we identified the pivotal roles of Sox2 as the master transcription factor in orchestrating the TIC-specific immune resistance program. Here, we will employ an ultrasound-guided in utero lentiviral gene delivery approach to achieve rapid genetic manipulation of TICs directly in spontaneous SCC tumors. With this powerful technique, we aim to first identify the Sox2-activated transcriptional network for shaping the immune suppressive microenvironment. Second, we will dissect the mechanisms of how Sox2 enhances the intrinsic immune resistance of tumor- initiating cells. Collectively, our proposed study will advance our understanding of the immune resistance mechanisms specific to TICs and how these mechanisms promote SCC relapse after immunotherapy treatment. Ultimately, defining the blueprints of the TIC-specific immune evasive mechanisms will open new avenues to overcome the SCCs recurrence and improve the efficacy of current cancer treatments.