Effects of Complement on the Tumor Microenvironment in Lung Cancer

肺癌是男性和女性癌症死亡的主要原因，而总存活率并不是 在过去的25年里，大多数患者的病情都有了显著的改善。逃避免疫攻击是一种 是癌症的标志，由癌细胞和肿瘤微环境之间的相互作用所调节 (TME)。已建立的肿瘤，包括肺癌，采用各种策略来阻止免疫攻击，以及 靶向这些通路已经显示出作为一种治疗方法的前景。虽然研究较少，但也有可能 这种免疫逃避是肿瘤发生的关键。补语系统是先天系统的一个组成部分 免疫系统，与适应性免疫系统接口。补体激活通过 三条主要途径：经典途径、替代途径和凝集素途径。所有这些都会引发一系列 蛋白水解级联在C3b共价固定到靶细胞表面的过程中聚合。沉积的C3b 导致C5转换酶的形成，该酶裂解C5产生C5a，最终形成C5b- 9，命名为膜攻击复合体(MAC)，可引起靶细胞的裂解。C3a和C5a (过敏性毒素)是补体激活的副产物，是一种炎症介质，与受体结合在一起。 TME的多个细胞。最初有人提出，通过抗体结合而启动的补体激活 癌细胞将通过依赖MAC杀死癌细胞来抑制癌症。然而，我们最近的研究， 小组和其他人已经表明，过敏毒素(C3a/C5a)，通过作用于 临时进入免疫逃逸通路。一种新的非小细胞原位免疫活性模型 肺癌(NSCLC)，我们已经证明补体在肺癌中被激活，并抑制补体 无论是从基因上还是从药物上都能阻止肿瘤的发展。然而，补体是如何激活的，以及 它是如何调控肿瘤进展的还不是很清楚。本项目将使用以下工具回答这些问题 肺癌发生和发展的相关模型与不同的致癌驱动因素。中心前提 这一应用的意义在于补体的激活直接促进了肺癌的发生和发展 通过直接作用于先天免疫细胞而导致免疫抑制的进展。MPI 该项目是在肺癌生物学方面有经验的研究人员(Nemenoff)和 补充生物学(瑟曼)。我们将采用一个创新的小鼠遗传模型小组，以及 评估补体在改变TME中的作用的新方法。提出了三个具体目标。 目的1将确定已建立的肺部肿瘤中补体激活的机制。Aim 2将研究 解毒毒素介导的分子和细胞机制。目标3将定义补语在 肿瘤的起源。该项目的完成将为未来的临床试验提供临床前数据 已为其他疾病开发的药理补体调节剂。

Lung cancer is the leading cause of cancer death in both men and women, and overall survival has not significantly improved over the last 25 years for the majority of patients. Evasion from immune attack is a hallmark of cancer and is mediated by interactions between cancer cells and the tumor microenvironment (TME). Established tumors, including lung cancer, adopt a variety of strategies to block immune attack, and targeting these pathways has shown promise as a therapeutic approach. While less studied, it is also likely that immunoevasion is critical for tumor initiation. The complement system is a component of the innate immune system, which interfaces with the adaptive immune system. Complement activation occurs through three major pathways: the classical, the alternative and the lectin pathway. All of these trigger a series of proteolytic cascades that converge in the covalent fixation of C3b to the surface of target cells. Deposited C3b leads to formation of the C5 convertase, which cleaves C5 to produce C5a and ultimately the formation of C5b- 9, designated the membrane attack complex (MAC), which can cause lysis of target cells. C3a and C5a (anaphylatoxins), byproducts of complement activation, are inflammatory mediators that bind to receptors on multiple cells of the TME. Initially it was proposed that activation of complement initiated by antibody binding to cancer cells would inhibit cancer by MAC-dependent killing of cancer cells. However, recent studies by our group and others have shown that anaphylatoxins (C3a/C5a), promote cancer progression by acting on the TME to engage immunoevasive pathways. Using a novel orthotopic immunocompetent model of non-small cell lung cancer (NSCLC), we have shown that complement is activated in lung tumors, and inhibiting complement either genetically or pharmacologically blocks tumor progression. However, how complement is activated and how it regulates tumor progression are not well understood. This project will answer these questions using relevant models of lung cancer initiation and progression with distinct oncogenic drivers. The central premise of this application is that activation of complement directly contributes to lung cancer initiation and progression through direct effects on innate immune cells leading to immunosuppression. The MPI project is a collaboration between investigators with experience in the biology of lung cancer (Nemenoff) and complement biology (Thurman). We will employ an innovative panel of genetic mouse models, as well as novel methodologies to assess the role of complement in altering the TME. Three specific aims are proposed. Aim 1 will identify mechanisms of complement activation in established lung tumors. Aim 2 will examine the molecular and cellular mechanisms mediated by anaphlyatoxins. Aim 3 will define the role of complement in tumor initiation. Completion of this project will provide preclinical data for future clinical trials using pharmacological complement modulators which have been developed for other diseases.