Chronic inflammation and immunosupression contribute to lung cancer formation. The long-term goal of this application is to identify the molecular and cellular mechanisms that control inflammation-induced tumorigenesis. Myeloid-derived suppressor cells (MDSCs) play a critical role in this process. MDSCs suppress T cell proliferation/function to subvert immune surveillance and prevent the immune system from eliminating tumor cells. Neutral lipid-derived hormones and their downstream nuclear receptors are keys to controlling the inflammation-induced MDSC surge and tumorigenesis. LAL hydrolyzes cholesteryl ester and triglycerides to generate free cholesterol and free fatty acids. Indeed, ablation of the lal gene resulted in systemic increase of MDSCs and immunosuppression of T cell proliferation/function in LAL knockout (lal-/-) mice. A defect in myelopoiesis with increased myeloid progenitor cells was observed in the lal-/- bone marrow. Adaptive bone marrow transplantation between wild type and lal-/- mice showed that both cell autonomous and tissue microenvironments contributed to abnormal MDSC development and homeostasis during LAL deficiency. To identify the molecular mechanism that controls these events, peroxisome proliferator-activated receptor gamma (PPAR?) appears to be a strong candidate. This is because 1) PPAR? is an anti-inflammatory agent;2) LAL-derived lipid metabolites serve as ligands to activate PPAR?;3) PPAR? negatively regulates inflammatory molecules that are up-regulated in lal-/- mice;4) PPAR? ligand treatment ameliorated inflammation and pathogenesis in lal-/- mice. The central hypothesis for the proposed studies is that the LAL/hormonal ligands/PPAR? axis in myeloid cells controls MDSCs development, homeostasis, immunosuppression and lung tumorigenesis. To test the central hypothesis and accomplish the goal of this application, two Specific Aims have been proposed.
Aim 1 will test a working hypothesis that PPAR? ligands are required for balancing anti- and pro-inflammation cascades in vivo by regulating myelopoiesis, MDSC expansion and immunosuppression. This will be accomplished by reintroducing PPAR? ligands into lal-/- mice to rescue inflammatory and pathogenic phenotypes. Effect of PPAR? ligand treatment on Lewis lung carcinoma engrafted tumor growth and metastases in lal-/- mice will be investigated;
Aim 2 will test a working hypothesis that PPAR? is required for balancing anti- and pro-inflammation cascades in vivo by regulating myelopoiesis, MDSC expansion and immunosuppression. This will be accomplished by overexpressing dnPPAR? in myeloid cells to inhibit the endogenous PPAR? function in c-fms-rtTA/(tetO)7-dnPPAR? bitransgenic mice to promote chronic inflammation and lung cancer. Since this model showed de novo tumorigenesis in the lung, bone marrow and MDSCs transplantation will be performed to test if MDSCs in this mouse model are directly responsible for tumorigenesis. Accomplishment of the proposed studies will elucidate the molecular mechanism by which the LAL/hormonal ligands/PPAR? axis controls anti-tumor adaptive immunity and pave the way for novel immunotherapy of lung cancer.
Chronic inflammation and immunosupression contribute to lung cancer. This proposal will utilize knock-out and transgenic animal models to identify the molecular and cellular mechanisms that control inflammation-induced tumor immunosuppression. Accomplishment of the proposed studies will elucidate the functional role of the LAL/hormonal ligands/PPAR? axis in anti-tumor adaptive immunity and pave the way for novel immunotherapy of lung cancer.
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|Zhao, Ting; Du, Hong; Blum, Janice S et al. (2016) Critical role of PPARÎ³ in myeloid-derived suppressor cell-stimulated cancer cell proliferation and metastasis. Oncotarget 7:1529-43|
|Du, Hong; Zhao, Ting; Ding, Xinchun et al. (2015) Hepatocyte-Specific Expression of Human Lysosome Acid Lipase Corrects Liver Inflammation and Tumor Metastasis in lal(-/-) Mice. Am J Pathol 185:2379-89|
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|Zhao, T; Du, H; Ding, X et al. (2015) Activation of mTOR pathway in myeloid-derived suppressor cells stimulates cancer cell proliferation and metastasis in lal(-/-) mice. Oncogene 34:1938-48|
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|Ding, Xinchun; Du, Hong; Yoder, Mervin C et al. (2014) Critical role of the mTOR pathway in development and function of myeloid-derived suppressor cells in lal-/- mice. Am J Pathol 184:397-408|
|Yan, Cong; Ding, Xinchun; Wu, Lingyan et al. (2013) Stat3 downstream gene product chitinase 3-like 1 is a potential biomarker of inflammation-induced lung cancer in multiple mouse lung tumor models and humans. PLoS One 8:e61984|
|Wu, Lingyan; Yan, Cong; Czader, Magdalena et al. (2012) Inhibition of PPARÎ³ in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis. Blood 119:115-26|
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