Effect of Cyclical Intermittent Hypoxia on Lung Cancer Progression

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Objective: To understand why older Veterans are at increased risk of lung cancer. Our overarching goal is to determine how T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSC), two major immune cells known to accumulate in lungs as we age, promotes lung cancer progression. Our hypothesis is that (Aim 1) old mice will have more Tregs and MDSCs in the lung compared to young mice, and this is more pronounced in the setting of lung cancer; (Aim 2) the increase in Tregs and MDSCs in old mice with cancer will compete for more nutrients that lead to decreased mTOR function in the surrounding normal lung around the cancer; (Aim 3) that the increased Tregs in old mice will consume more nutrients (arginine) and further promote lung cancer progression. Research Design: We will use the same mouse models of lung cancer in the Parent Merit, where Triple Transgenic KrasG12D+; p53fl/fl; myristoylated p110fl/fl ROSA-gfp (TT-Kpp) mice are injected with cre viruses (Kras POS mice) and injected with clone cells (Kras NEG mice). The conceptual innovation of this grant is that we will be the first to explore the interaction between cancerous lung and normal lung in old vs young mice, specifically the metabolic pathway, mTOR and nutrient competition, arginine, as they both promote an increase in immunosuppression and the progression of cancer. Methodology: Aim 1: To identify immune cell phenotype in the lungs of old versus young mice with lung cancer. Primary outcome will be quantitative M-MDSC/TAM/Tregs in the left lung at early (2 mm) and late (>4 mm) time points. Aim 2: To evaluate the role of the mTOR pathway on immune and senescent cell populations in old versus young mice with lung cancer. Primary outcome will be quantitative 4EBP in normal lung surrounding the lung cancer compared to that within the cancer in old vs young mice. Aim 3: To explore the relationship between MDSCs, ARG1, and arginine levels in old versus young mice with lung cancer. Primary outcome will be quantitative M-MDSC in the left lung at early (2 mm) and late (>4 mm) time points. Exploratory: To determine the feasibility of administering inhaled host-directed therapies (HDT) intended on disrupting SPIRAL using 4D scanner. Findings: First submission. Clinical Relationships: We may provide evidence how immunosenescence in older patients contribute to lung cancer progression. Impact/Significance: By understanding Senescence-Provoked Immunometabolic Regulation in Lung Cancer, we may develop a novel treatment approach to lung cancer: deliver more nutrients to normal, non-cancerous lung.