Inflammation and Immunosuppression in Lung Cancer

描述（由申请人提供）：慢性炎症和免疫抑制有助于肺癌形成。 本申请的长期目标是确定控制炎症诱导的肿瘤发生的分子和细胞机制。 骨髓源性抑制细胞（MDSC）在这一过程中起着关键作用。 MDSC抑制T细胞增殖/功能以破坏免疫监视并阻止免疫系统消除肿瘤细胞。 中性脂源性激素及其下游核受体是控制炎症诱导的MDSC激增和肿瘤发生的关键。 LAL水解胆固醇酯和甘油三酯以产生游离胆固醇和游离脂肪酸。 事实上，在LAL敲除（lal-/-）小鼠中，lal基因的消融导致MDSC的系统性增加和T细胞增殖/功能的免疫抑制。 在lal-/-骨髓中观察到髓系祖细胞增加的骨髓生成缺陷。 野生型和lal-/-小鼠之间的适应性骨髓移植表明，细胞自主性和组织微环境导致LAL缺乏期间MDSC发育和稳态异常。 为了确定控制这些事件的分子机制，过氧化物酶体增殖物激活受体γ（PPAR？）似乎是一个强有力的候选人。 这是因为（1）PPAR？是一种抗炎剂; 2）LAL衍生的脂质代谢产物作为配体激活PPAR？; 3)PPAR？负调节炎症分子，上调lal-/-小鼠; 4）过氧化物酶体增殖物激活受体？配体治疗改善了LA 1-/-小鼠的炎症和发病机制。 拟议的研究的中心假设是，LAL/激素配体/过氧化物酶体增殖物激活受体？骨髓细胞中的MDSC轴控制MDSC发育、稳态、免疫抑制和肺肿瘤发生。 为了检验中心假设并实现本申请的目标，提出了两个具体目标。目的1将测试一个工作假设，过氧化物酶体增殖物激活受体？配体是通过调节骨髓生成、MDSC扩增和免疫抑制来平衡体内抗炎和促炎级联反应所必需的。 这将通过重新引入PPAR来实现？将配体导入LA 1-/-小鼠中以拯救炎性和致病性表型。 对PPAR？将研究配体治疗对lal-/-小鼠中刘易斯肺癌移植的肿瘤生长和转移的影响;目的2将检验工作假设，即PPAR？是通过调节骨髓生成、MDSC扩增和免疫抑制来平衡体内抗炎和促炎级联反应所必需的。 这将通过过度表达dnPPAR？抑制内源性过氧化物酶体增殖物激活受体？在c-fms-rtTA/（tetO）7-dnPPAR中的功能？双转基因小鼠促进慢性炎症和肺癌。 由于该模型显示肺中的新生肿瘤发生，因此将进行骨髓和MDSC移植以测试该小鼠模型中的MDSC是否直接导致肿瘤发生。 完成拟议的研究将阐明的分子机制，LAL/激素配体/过氧化物酶体激活受体？轴控制抗肿瘤适应性免疫，为肺癌的新型免疫治疗铺平了道路。

DESCRIPTION (provided by applicant): 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.