Effects of Complement on the Tumor Microenvironment in Lung Cancer

补体对肺癌肿瘤微环境的影响

基本信息

批准号：
10303019
负责人：
RAPHAEL A. NEMENOFF
金额：
$ 39.49万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-11 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10303019
关键词：
Adaptive Immune System Adopted Affect Anaphylatoxins Antibodies Binding Biology C3AR1 gene Cancer Etiology Cell Surface Receptors Cells Cessation of life Clinical Clinical Trials Collaborations Complement Complement 3 Convertase Complement 3a Complement 3b Complement 5a Complement Activation Complement Factor H Complement Membrane Attack Complex Cytolysis Data Deposition Disease Distant Equilibrium Event Future Generations Genetic Grant Growth Human Immune Immune Evasion Immune response Immunocompetent Immunoglobulins Immunosuppression Immunotherapy Implant Inflammation Mediators Inflammatory Innate Immune System Lectin Lesion Lobe Lung Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediastinal lymph node group Mediating Methodology Modeling Molecular Molecular Target Mus Myeloid Cells Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oncogenic Organ PD-1/PD-L1 Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phosphotransferases Play Population Primary Neoplasm Production Proteins Publishing Regulation Research Personnel Resistance development Role Series Site Surface T-Lymphocyte Testing Therapeutic Time Tissue Microarray Tumor Immunity Tumor stage Woman adaptive immune response adaptive immunity base cancer cell cancer initiation cellular targeting clinical development complement system crizotinib experience experimental study genetic regulatory protein human disease immune checkpoint improved inhibitor innovation lung cancer cell men mouse model neoplastic cell novel novel strategies pre-clinical precision medicine receptor response sample fixation targeted treatment therapy resistant tumor tumor growth tumor initiation tumor microenvironment tumor progression tumorigenesis

项目摘要

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.

肺癌是男性和女性癌症死亡的主要原因，而总体生存率却没有下降大多数患者的病情在过去 25 年中显着改善。逃避免疫攻击是一种癌症的标志，由癌细胞和肿瘤微环境之间的相互作用介导（TME）。已形成的肿瘤，包括肺癌，采用多种策略来阻止免疫攻击，并且针对这些途径已显示出作为一种治疗方法的前景。虽然研究较少，但也有可能免疫逃避对于肿瘤的发生至关重要。补体系统是先天性的一个组成部分免疫系统，与适应性免疫系统相互作用。补体激活通过以下方式发生三种主要途径：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汇聚 C3b 共价固定到靶细胞表面。存入C3b 导致 C5 转化酶的形成，该酶裂解 C5 产生 C5a，并最终形成 C5b- 9，指定膜攻击复合物（MAC），它可以引起靶细胞裂解。 C3a 和 C5a （过敏毒素）是补体激活的副产物，是与受体结合的炎症介质 TME 的多个细胞。最初有人提出，补体的激活是由抗体结合引发的。癌细胞会通过 MAC 依赖性杀死癌细胞来抑制癌症。然而，我们最近的研究研究小组和其他人已经表明，过敏毒素（C3a/C5a）通过作用于 TME 参与免疫逃避途径。使用新型非小细胞原位免疫活性模型肺癌（NSCLC）中，我们已经证明补体在肺部肿瘤中被激活，并且抑制补体从遗传上或药理学上阻断肿瘤进展。然而，补体如何被激活以及它如何调节肿瘤进展尚不清楚。该项目将使用以下方式回答这些问题具有不同致癌驱动因素的肺癌发生和进展的相关模型。中心前提该应用的关键在于补体的激活直接有助于肺癌的发生和通过直接影响先天免疫细胞导致免疫抑制而进展。初级产业部该项目是具有肺癌生物学经验的研究人员（Nemenoff）和补充生物学（瑟曼）。我们将采用一组创新的基因小鼠模型，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。目标 1 将确定已形成的肺部肿瘤中补体激活的机制。目标 2 将检查过敏毒素介导的分子和细胞机制。目标 3 将定义补体的作用肿瘤起始。该项目的完成将为未来的临床试验提供临床前数据已针对其他疾病开发的药理补体调节剂。