Deaths from lung cancer are the highest of all cancers in the US. The complexity of lung cancer (LC) development suggests that a combination of approaches is needed to understand the mechanism of LC biology and tumor cell interactions with other cells such as immune cells within the tumor microenvironment. The concept of """"""""cancer immunoediting"""""""" recognizes the complex and dynamic interactions between the tumor and host during tumor development, progression and metastasis. Although how the immune system plays a role in development and progression of human non-small cell lung carcinoma (NSCLC) is still elusive, innate macrophages are abundant in the NSCLC tumors. These macrophages are of immune suppressive M2 phenotype, promote tumor angiogenesis and metastasis and limit efficacy of chemotherapy for NSCLC. beta-Glucans, polysaccharides derived from various sources, can stimulate both innate and adaptive immune responses. Our preliminary data further demonstrate that beta-glucan treatment in vitro converts immune suppressive M2 macrophages into tumoricidal M1 phenotype and significantly decreases tumor-associated macrophage (TAM)-mediated immune suppression on CD4 and CDS T cells. Using the stable isotope resolved metabolomics (SIRM) approach, we show that glutamine (Gin) uptake and subsequent metabolism to glucose, glutathiones and lactate are enhanced when immune suppressive M2 macrophages are converted into an Ml phenotype. The central hvpothesis of this proposal is that differential human NSCLC subtypes may have distinct metabolic profiles and p-glucan treatment modulates TAM activity and metabolism, leading to the alterations of metabolic networks in NSCLC. We will use stable isotopic (13C, 15N) nutrient tracers in combination with the SIRM approach and metabolomics-edited transcriptomic analysis (META) to define key metabolic components of human NSCLC in vivo and investigate how beta-glucan treatment influences TAM phenotype, function, metabolism and subsequently tumor microenvironmental metabolic events.
Three Specific Aims are proposed to determine the: 1 specific metabolic patterns of human NSCLC cells in xenografted tumors in severe combined immunodeficient (SCID) mice;2) biochemical mechanisms of beta-glucan action in murine lung carcinoma models;3) biochemical and phenotypic characteristics of human primary tumors implanted in N0D/SCID/IL-2gcNULL mice in response to beta-glucan administration. These investigations will advance our understanding of the biochemical underpinnings of tumor microenvironment nutrient utilization by NSCLC and how these processes are related to tumor immune evasion and immunomodulation.

Public Health Relevance

Deaths from lung cancer are the highest among all cancers in North America and cure rates remain low. We seek to gain a deeper understanding of lung cancer biochemistry using a novel approach we developed. Improved knowledge will have direct impact on early diagnosis and prognosis. The biochemical differences between lung cancer subtypes can be related to appropriate treatments.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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University of Louisville
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Fan, Teresa W-M; Warmoes, Marc O; Sun, Qiushi et al. (2016) Distinctly perturbed metabolic networks underlie differential tumor tissue damages induced by immune modulator β-glucan in a two-case ex vivo non-small-cell lung cancer study. Cold Spring Harb Mol Case Stud 2:a000893
Albeituni, Sabrin H; Ding, Chuanlin; Liu, Min et al. (2016) Yeast-Derived Particulate β-Glucan Treatment Subverts the Suppression of Myeloid-Derived Suppressor Cells (MDSC) by Inducing Polymorphonuclear MDSC Apoptosis and Monocytic MDSC Differentiation to APC in Cancer. J Immunol 196:2167-80
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Lane, Andrew N; Higashi, Richard M; Fan, Teresa W-M (2016) Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM). Metabolomics 12:
Krem, Maxwell M; Yan, Jun (2016) To b(ortezomib) or not to be: the stroma's the thing. J Pathol 240:123-5
Fan, Teresa W-M; Lane, Andrew N (2016) Applications of NMR spectroscopy to systems biochemistry. Prog Nucl Magn Reson Spectrosc 92-93:18-53
Fan, Teresa W-M; Lane, Andrew N; Higashi, Richard M (2016) Stable Isotope Resolved Metabolomics Studies in Ex Vivo TIssue Slices. Bio Protoc 6:
Lane, Andrew N; Arumugam, Sengodagounder; Lorkiewicz, Pawel K et al. (2015) Chemoselective detection and discrimination of carbonyl-containing compounds in metabolite mixtures by 1H-detected 15N nuclear magnetic resonance. Magn Reson Chem 53:337-43
Liu, Min; Luo, Fengling; Ding, Chuanlin et al. (2015) Dectin-1 Activation by a Natural Product β-Glucan Converts Immunosuppressive Macrophages into an M1-like Phenotype. J Immunol 195:5055-65
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