Tumor-Targeted STING Agonism in Head and Neck Squamous Cell Carcinoma

Yale University, New Haven CT

Investigators

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a lethal disease that kills ~200,000 people annually worldwide. Resistance to DNA-damaging agents (i.e. radiation therapy [RT] and chemotherapy) is a significant problem in both the locally advanced and recurrent/metastatic settings, ultimately leading to patient death. Attempts to improve responses to DNA damaging agents with programmed death-1 (PD-1) axis agents have been limited, indicating the crucial need to identify novel determinants of the DNA damage response (DDR). Towards this end, through use of a whole-genome CRISPR screen, we have uncovered a novel role for tumor STING (stimulator of interferon genes) as a critical determinant of the tumor cell intrinsic response to DNA damage. We show that loss of STING expression enhances tumor cell intrinsic resistance to DNA-damaging therapies through alterations in reactive oxygen species (ROS) homeostasis and DNA damage, and conversely that activation of STING enhances ROS generation. To overcome poor pharmacokinetics (PK) and lack of tumor- targeting that have led to the failed clinical use of current STING agonists (STINGa) we have developed a novel tumor-targeted STINGa using pHLIP (pH low insertion peptide). pHLIP is a clinically utilized technology that takes advantage of the acidic tumor microenvironment (TME) and delivers its cargo specifically to the tumor and TME. In our preliminary data we show that STING activation with pHLIP-STINGa enhances the effects of DNA- damage in a biomarker (tumor STING)-dependent manner, resulting in tumor cure. Based upon these preliminary data we will test the hypothesis that STING serves as an actionable target to enhance the effects of DNA-damaging therapy through modulation of tumor intrinsic (ROS and DNA damage) and immune-mediated responses in a tumor STING dependent manner. In Aim 1 we will develop an optimized tumor-targeted, dimeric pHLIP-STINGa to overcome the major shortcomings of existing failed STINGa, thus allowing for clinical translation of these findings. In Aim 2 we will test the hypothesis that pHLIP-STINGa will synergize with ROS-dependent DNA damaging therapies in a tumor STING-dependent manner and dissect the mechanism of STING in regulating ROS and DNA damage levels. These studies will further our biologic understanding of the interaction of the innate immune machinery and cell intrinsic DDR with the potential to guide therapy selection. Lastly, in Aim 3 we will use pHLIP-STINGa to identify the immunologic mechanisms of the tumor STING-dependent control of DNA-damaging therapy and PD-1 combinations in HNSCC. We will test the hypothesis that the increased tumor killing seen with pHLIP-STINGa + DNA-damage combinations will enhance responses to PD-1 axis agents in otherwise resistant, immunologically cold HSCC . We will also define forced STING re-expression by DNA methyltransferase inhibition as a strategy to restore sensitivity to pHLIP-STINGa combinations in STING-deficient HNSCC. The long-term goal of this study is to translate our findings into a clinical trial that tests pHLIP STINGa + DNA damaging therapy treatment combinations in HNSCC.