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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：
9913473
负责人：
DONALD W. KUFE
金额：
$ 62.43万
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/9913473
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 PD-1 blockade PD-1/PD-L1 PD-L1 blockade PDL1 pathway Pathogenesis Pathway interactions Patients Phenotype Play Polymers Primary Neoplasm Production Proteins Receptor Activation Receptor Signaling Research Resected Role Shapes Signal Pathway Signal Transduction Specimen T-Lymphocyte Therapeutic Agents Tumor-associated macrophages Tumorigenicity United States Work base cancer cell cancer genomics cancer therapy cytokine effective therapy extracellular gene therapy immune checkpoint improved inhibitor/antagonist macrophage mutant nanoparticle novel novel strategies outcome forecast overexpression programmed cell death ligand 1 recruit 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），特别是那些激活KRAS突变的肺癌