Co-Option of Alveolar Macrophage Homeostatic Metabolic Networks in Lung Adenocarcinoma
Date of Award
Doctor of Philosophy (PhD)
Cancer, fundamentally a disease of deregulated tissue homeostasis, substantially alters the composition of the surrounding tumor microenvironment (TME). The metabolic demands for rapid cellular growth and proliferation result in abnormally high rates of glucose and amino acid consumption in cancer cells. We propose a model in which nutrient competition creates a metabolic checkpoint engendering a suppressive TME. Failure to acquire adequate nutrients is compounded by the accumulation of nutritionally—and therefore immunologically—permissive immune cells. In Chapter 2, using a genetically induced mouse model of lung adenocarcinoma, we observed a striking expansion in resident alveolar macrophages (AM). AM accumulation was dependent upon increased expression of GM-CSF from transformed type II pneumocytes (AT2). As tumors progressed, these macrophages up-regulated surface expression of markers associated with alternative activation, decreased their production of inflammatory cytokines, and increased their lipid uptake and storage. Increased lipid metabolism corresponded to an increase in surfactant proteins and lipids within the bronchial alveolar lavage fluid. PPARγ skews AMs, and other macrophages, towards an anti-inflammatory state, integrating metabolic signals and inflammatory outcome. Pharmacological and genetic inhibition of PPARγ delayed tumor progression while restoring AMs’ inflammatory cytokine production. We suggest that PPARγ facilitates an important role in regulating the metabolic and inflammatory states of tumor-associated AMs making them uniquely suited to thrive within the TME. In Chapter 3, we further explore the relationship between macrophage and tumor cell metabolism. We identified global changes in lipid metabolism in tumor cells from the tumors of mice with PPARγ-/- AMs: The cells instead increased lipid synthesis and decreased lipid import. We propose a model in which decreases in cholesterol efflux from PPARγ-/- AMs limit cholesterol availability for tumor cells, stimulating these alterations. We then discuss the future directions and implications that identifying this paracrine metabolic and immunologic loop between macrophages and tumor cells would have for future therapies.In Chapter 4, we look at the immune response during tumor regression mediated by the currently approved targeted therapy against EGFR, osimertinib. We found that the increasingly suppressive tumor microenvironment was partially reversed following TKI with increased infiltration of T cells, monocytes and neutrophils and decreased accumulation of AMs. While we did see a restoration in both innate and adaptive cells effector cytokine production, treatment did not reverse expression of inhibitory receptors on either cell types. However, despite the continued expression of checkpoint molecules, we did not observe a synergistic effect with anti-PD-L1 therapy, though we did see an increase in monocytes and neutrophils when used in conjunction. This descriptive study established the immune response to osimertinib, which further informs additional strategies to combine immunotherapy and TKIs in EGFR mutant LUAD. Collectively, this work adds to our knowledge of the complex role that the immune system has in mediating tumor progression and response to therapy.
Kuhlmann, Alexandra, "Co-Option of Alveolar Macrophage Homeostatic Metabolic Networks in Lung Adenocarcinoma" (2022). Yale Graduate School of Arts and Sciences Dissertations. 489.