Inflammation and Immunosuppression in Lung Cancer

描述(申请人提供)：慢性炎症和免疫抑制导致肺癌的形成。这项应用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。髓系来源的抑制细胞(MDSCs)在这一过程中起着关键作用。MDSCs抑制T细胞的增殖/功能，破坏免疫监视，阻止免疫系统清除肿瘤细胞。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能分解胆固醇酯和甘油三酯，产生游离胆固醇和游离脂肪酸。事实上，去除Lal基因导致了Lal基因敲除(Lal-/-)小鼠MDSCs的全身性增加和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多的骨髓生成缺陷。野生型和Lal-/-小鼠之间的适应性骨髓移植表明，在Lal缺乏期间，细胞自主和组织微环境都有助于MDSC的异常发育和体内平衡。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？2)LAL衍生的脂质代谢产物作为配体激活PPAR？；3)PPAR？负向调节LAL-/-小鼠上调的炎性分子；4)PPAR？配体治疗可改善LAL-/-小鼠的炎症反应和发病机制。建议研究的中心假设是LAL/激素配体/PPAR？髓系细胞中的AXIS控制MDSCs的发育、动态平衡、免疫抑制和肺肿瘤的发生。为了检验中心假设并实现本应用的目标，本文提出了两个具体目标。目标1将检验一个工作假说，即PPAR？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来实现吗？配体进入LAL-/-小鼠以挽救炎症和致病表型。PPAR的效果如何？Lal-/-小鼠Lewis肺癌移植瘤生长和转移的配体治疗将被研究；Aim 2将检验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来实现吗？在髓系细胞中抑制内源性PPAR？C-fms-rtta/(Teto)7-dnPPAR？促进慢性炎症和肺癌的双转基因小鼠。由于该模型显示新生肿瘤发生在肺中，将进行骨髓和MDSCs移植，以测试该小鼠模型中的MDSCs是否直接导致肿瘤发生。拟议研究的完成将阐明LAL/激素配体/PPAR？AXIS调控抗肿瘤获得性免疫，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.