Lung cancer is responsible for more deaths in the United States than any other form of cancer. Unfortunately, many lung cancer patients do not respond to treatments that effectively mobilize cytotoxic T cells against tumors in other cancers (e.g. anti-PD-1/PD-L1 and anti-CTLA4). This lack of response in lung cancer is primarily due to an inability to initiate a robust antitumor immune response. Lung cancer cells secrete the damage-associated molecular pattern protein, High Mobility Group Box 1 (HMGB1) which has a dual function in immunity. Although it can facilitate immune cell infiltration into tumors; its predominant function is to drive the secretion of negative immune regulators including TGF-b and IL-10 and increase expression of programmed death receptor ligand 1 (PD-L1). My preliminary data suggest that monounsaturated fatty acids (MUFA) are required to prevent HMGB1 secretion from lung cancer cells. Therefore, I hypothesize that lung cancer patients with lower concentrations of tumor-associated MUFA will have higher expression of HMGB1 resulting in an immunosuppressive tumor microenvironment (TME). To test this hypothesis, I propose two Specific Aims: 1) Determine the association between MUFA, extracellular HMGB1, and lung cancer in patients; 2) Evaluate the effects of MUFA on secretion of HMGB1 and the activation of cancer-associated fibroblasts in ex vivo tumor models. I will use lipidomic and immunological assays to determine the association between MUFA and secreted HMGB1 in lung cancer patients. Using patient tissue explants, I will measure the effects of pharmacologic inhibition of MUFA on secretion of HMGB1. To study the effects of genetic and pharmacologic inhibition of MUFA on the TME, I will construct vascularized 3-dimensional bioprinted lung tumors constructed using lung cancer cells and lung fibroblasts. This will allow characterization of immune modulating cytokines secreted by cancer-associated fibroblasts, a dominant cell type within lung tumors. The long-term goal of this research is to provide insight into the mechanisms by which tumors orchestrate immune suppression, and enable the development of new strategies to overcome this immunological barrier. This K01 proposal is designed to build upon my training background and track record in basic molecular and cancer biology, and expand my skills as a translational researcher. My scientific advisory committee is composed of accomplished scientists and clinicians with expertise in oncology, lung disease, lipid biochemistry, fibroblast biology and molecular biology. The program outlined in this K01 proposal will propel me into an independent scientific career through rigorous career development activities tailored to my specific research goals.

Project Narrative Although, treatment of lung cancer has improved in recent years, the majority of patients will still succumb to this disease. Improving our understanding of the tumor microenvironment will increase our ability to reactivate the natural defense mechanisms that are silenced in patients with malignant tumors. The goal of this work is to learn how to harness lipids to improve tumor immunity and sensitivity to currently available cancer therapies.