Objective: Lung cancer continues to have a very poor prognosis, with Veterans having a higher incidence of lung cancer and worse outcome compared to civilians.1 Obstructive sleep apnea (OSA) has been associated with higher cancer incidence2-5 and mortality,2, 6-8 and again, Veterans have a higher prevalence of OSA that is more severe compared to civilians.9 Our overarching objective is to determine how cyclical intermittent hypoxia (CIH), a major underlying pathology of OSA, promotes lung cancer progression. Our hypothesis is that CIH increases the differentiation of immature immune cells to suppressor immune cells which then, inadvertently, protects the cancer. We have published that CIH accelerates primary lung cancer progression in Triple Transgenic KrasG12D+; p53fl/fl; myristolated p110fl/fl ROSA-gfp (TT-Kpp) mice (funded by VA CPPF grant). This grant is the next step - to explore mechanisms of HOW CIH promotes cancer progression. Research Design: The technical innovation of this grant is that we will be the first to measure the effect of mild, moderate and severe CIH on cancer progression in TT-Kpp mice (Aim 1). The conceptual innovation of this grant is that we will be the first to use this TT-Kpp model to explore whether systemic CIH increases production, differentiation and recruitment of suppressor immune cells to primary lung cancer. Methodology:
Aim 1 : TT-Kpp mice injected with Ad5CC10Cre virus will be exposed to one of 4 conditions: sham (room air), mild CIH (CIH15, (drops in FiO2 0.21 to FiO2 0.15 [SaO2 nadir of 82%]) moderate CIH (CIH10, (drops in FiO2 0.21 to FiO2 0.15 [SaO2 nadir of 61%]) or severe CIH (CIH5; drops in FiO2 0.21 to FiO2 0.05 [SaO2 nadir of 37%]). Primary outcome will be quantitative tumor volumes (monthly microCT scans); secondary outcome will be survival.
Aim 2 : Assess the effect of CIH5 (vs Sham) on production, differentiation and recruitment of suppressor immune cells in mice with and without cancer. Primary outcome will be quantitative M-MDSC/TAM/Tregs in bone marrow, spleen, thymus, left lung and right lung at early (2 weeks) and late (4 months) time points; secondary outcome will be functional assays of suppressor immune cells. Exploratory Aim 3: Develop a clone cancer cell from lung cancer of TT-Kpp mice. Also, assess the effect of CIH5 (vs Sham) regulating (1) chemokine/cytokine genes within lung cancer cell (via PCR panel at early and late time point) and (2) other genes (via RNA-seq at one time point). Together, the PCR and RNA-seq information will be utilized in a future grant where we will use CRISPR editing of significant genes within clone cells and inject them into a wild type mouse (syngeneic orthotopic model) to further understand mechanism of effect of CIH on cancer progression. Findings: First submission. Clinical Relationships: We may provide evidence that CIH, a major pathology of obstructive sleep apnea, is a modifiable risk factor that can improve lung cancer survival. Impact/Significance: Positive airway pressure, a treatment for OSA has no side effects and may be a powerful adjunct therapy to prevent lung cancer progression.

Public Health Relevance

Lung cancer has a low survival rate, and Veterans not only have a higher rate of lung cancer but also, a worse outcome compared to civilians. Obstructive sleep apnea (OSA) has been linked to higher rates of cancer and cancer death, and again, Veterans not only has a higher rate of OSA but also, their OSA is more severe compared to civilians. Cyclical intermittent hypoxia (CIH) is where oxygen levels go from normal to low many times a night as seen in patients with OSA. We have developed and demonstrated in a mouse model of lung cancer that when mice are exposed to CIH, CIH does make the lung cancer grow faster. In this grant we want to know how CIH makes the cancer grow faster, specifically, how CIH might hijack the immune system to protect the cancer instead of killing the cancer.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Special Emphasis Panel (ZRD1)
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Miami VA Health Care System
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