MUC1-C Oncoprotein Evades Immune Destruction in Non-small Cell Lung Cancer

MUC1-C 癌蛋白在非小细胞肺癌中逃避免疫破坏

基本信息

批准号：
9544460
负责人：
DONALD W. KUFE
金额：
$ 12.6万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9544460
关键词：
Address Adenocarcinoma Antibodies Antibody-drug conjugates Beds Biopsy C-terminal Cancer Etiology Cancer Patient Cancer cell line Cell physiology Cells Cessation of life Cytoplasmic Tail Development Disease Epidermal Growth Factor Receptor Extracellular Domain Gene Expression Genetically Engineered Mouse Glycoproteins Grant Human Immune Immune Evasion Immune signaling Immunocompetent Immunotherapeutic agent In Vitro Infiltration Inflammation Investigation KRAS2 gene Link Malignant Neoplasms Malignant neoplasm of lung Monoclonal Antibodies Mucin 1 protein Mucins Mutation N-terminal Non-Small-Cell Lung Carcinoma Oncogenic Oncoproteins PDCD1LG1 gene Pathogenesis Pathway interactions Patients Phenotype Play Polymers Primary Neoplasm Production Proteins Receptor Activation Receptor Signaling Recruitment Activity Research Resected Role Shapes Signal Pathway Signal Transduction Specimen T-Lymphocyte Therapeutic Agents Tumorigenicity United States Work base cancer cell cancer genomics cancer therapy cytokine effective therapy extracellular immune checkpoint improved inhibitor/antagonist macrophage mouse model mutant nanoparticle novel novel strategies outcome forecast overexpression response self-renewal targeted agent targeted treatment therapeutic target treatment strategy tumor tumor microenvironment tumor xenograft

项目摘要

Non-small cell lung cancers (NSCLCs), particularly those with activating KRAS mutations, are often unresponsive to targeted agents and have a poor prognosis. However, immunotherapeutic approaches, particularly PD-1/PD-L1 pathway blockade, have recently improved the treatment of these cancers, supporting the premise that evasion of immune destruction contributes to NSCLC pathogenesis. MUC1-C is an oncogenic protein that is overexpressed in >80% of NSCLCs and is linked to multiple immune signaling pathways. Work supported by this grant has demonstrated that EGFR mutant NSCLCs activate the PD-1/PD-L1 pathway and increase production of proinflammatory cytokines. We have also shown that MUC1-C promotes (i) oncogenic signaling in NSCLCs via EGFR activation, and (ii) confers EMT, self-renewal and tumorigenicity in KRAS mutant NSCLCs. Based on these findings, we have generated novel antibodies against the non-shed MUC1-C extracellular domain and inhibitors of the cytoplasmic domain for therapeutic targeting of MUC1-C in NSCLC cells. Our preliminary observations indicate that targeting MUC1-C downregulates PD-L1 expression in EGFR and KRAS mutant NSCLC cells. We have also found that MUC1-C deficiency is associated with recruitment of tumor-associated macrophages and alterations in the infiltrating T-cell phenotype. Our hypothesis is that MUC1-C plays an important role in evading immune destruction, which will be addressed in studies of (i) human NSCLC cell lines, (ii) genetically engineered mouse models, and (iii) primary NSCLC tumors. The Specific Aims are: (1) To investigate the role of MUC1-C in PD-L1 pathway activation in EGFR and KRAS mutant NSCLC cells, (2) To define the role of MUC1-C in recruitment and function of macrophages and T-cells within the tumor microenvironment of KRAS and EGFR mutant NSCLC, (3) To evaluate the effects of targeting MUC1-C to circumvent immune evasion in mutant EGFR and KRAS NSCL tumors, and (4) To assess fresh resected/biopsied lung cancer specimens and correlate MUC1 expression with T-cell and other immune cell infiltration, immune checkpoint gene expression, and cytokine secretion in the tumor microenvironment.

非小细胞肺癌（NSCLC），尤其是激活KRAS突变的细胞癌，通常是对靶向药物无反应，预后不良。但是，免疫治疗方法，特别是PD-1/PD-L1途径封锁，最近改善了这些癌症的治疗逃避免疫破坏有助于NSCLC发病机理的前提。 MUC1-C是一个 > 80％的NSCLC中过表达的致癌蛋白，并与多个免疫信号相关途径。该赠款支持的工作表明，EGFR突变体NSCLC激活PD-1/PD-L1途径并增加促炎细胞因子的产生。我们还表明，MUC1-C促进（i） NSCLC中通过EGFR激活中的致癌信号传导，（ii）赋予EMT，自我更新和肿瘤性。 KRAS突变NSCLC。基于这些发现，我们已经生成了针对非侵蚀的新抗体 MUC1-C细胞外结构域和细胞质结构域的抑制剂，用于MUC1-C在中的治疗靶向 NSCLC细胞。我们的初步观察结果表明，靶向MUC1-C下调EGFR中的PD-L1表达 KRAS突变NSCLC细胞。我们还发现，MUC1-C缺乏症与招募有关肿瘤相关的巨噬细胞和浸润T细胞表型的改变。我们的假设是 MUC1-C在逃避免疫破坏中起着重要作用，这将在（i）的研究中解决人NSCLC细胞系，（ii）基因工程的小鼠模型和（iii）原发性NSCLC肿瘤。具体目的是：（1）研究MUC1-C在EGFR和KRAS中PD-L1途径激活中的作用突变的NSCLC细胞，（2）定义MUC1-C在巨噬细胞和T细胞募集和功能中的作用在KRAS和EGFR突变体NSCLC的肿瘤微环境中，（3）评估靶向的影响 MUC1-C绕过突变体EGFR和KRAS NSCL肿瘤的免疫逃避，（4）评估新鲜切除/活检的肺癌标本，并将MUC1表达与T细胞和其他免疫细胞相关联肿瘤微环境中的浸润，免疫检查点基因表达和细胞因子分泌。