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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：
10521237
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10521237
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 Phosphotransferases Play Population Primary Neoplasm Probability 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 cancer cell cancer initiation cellular targeting clinical development complement system crizotinib examination questions experience experimental study genetic regulatory protein human disease immune checkpoint improved inhibitor innovation lung cancer cell men mouse model neoplastic neoplastic cell novel novel strategies pharmacologic pre-clinical precision medicine receptor response sample fixation targeted treatment therapy resistant tumor tumor growth tumor initiation tumor microenvironment tumor progression tumor-immune system interactions 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，但总体生存率却没有变化