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Immune Regulation of Lung Squamous Metastasis

肺鳞状细胞癌的免疫调节

基本信息

批准号：
10237317
负责人：
Chad V Pecot
金额：
$ 38.77万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-21 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237317
关键词：
Accounting Antibodies Biology CCL2 gene CCL3 gene CSF1 gene Cancer Etiology Cell Death Cell Line Cell physiology Cessation of life Clinical Coculture Techniques Data Deposition Development Distant Metastasis Epigenetic Process Fibrin Genes Growth Growth and Development function Immune Evasion Immune Targeting Immune checkpoint inhibitor Immunocompetent Immunologics Immunosuppression Immunotherapy Infiltration Inflammation Mediators Inflammatory Interruption Lead Ligands Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mediating MicroRNAs Modeling Molecular Molecular Profiling Mus Neoplasm Metastasis Ontology Operative Surgical Procedures Outcome Pathway interactions Patients Play Process Proteins Research Resected Role Sampling Signal Transduction Squamous Cell Lung Carcinoma TNF gene The Cancer Genome Atlas Therapeutic Tissue Microarray Treatment Efficacy Tumor-associated macrophages Update angiogenesis cancer type chemokine chemotherapy efficacy evaluation engineered T cells experience experimental study immune checkpoint blockade immunoregulation improved in vivo inhibitor/antagonist monocyte novel novel therapeutic intervention paracrine programmed cell death ligand 1 programmed cell death protein 1 programs recruit response targeted treatment tumor tumor growth tumor microenvironment

项目摘要

Project Summary: Lung cancer is the leading cause of cancer-related deaths in the U.S., accounting for 158,040 deaths in 2015. While targeted therapies of lung adenocarcinoma have improved overall survival, similar advances in lung squamous carcinoma (LUSC) have been stagnant. Extensive molecular profiling through the Cancer Genome Atlas (TCGA) effort revealed that LUSC tumors are highly idiosyncratic and rarely driven by solitary actionable pathways. However, the tumor microenvironment (TME), which promotes the metastasis that accounts for 90 percent of cancer-related deaths, remains an attractive target for immune-based therapies. Recently, the blockade of immune checkpoints with anti-Programed cell death protein 1 (PD1) antibodies has demonstrated remarkable therapeutic promise in LUSC patients, with about 20% of unselected patients experiencing durable responses. Thus, a more complete understanding of how the tumor microenvironment (TME) promotes LUSC will allow us to build upon these advances. Using updated TCGA data for LUSC, we have uncovered a previously unidentified subset of LUSC characterized by infiltration of inflammatory monocytes (IMs). This subset accounts for nearly half of all LUSC patients, is associated with very poor outcome, and has numerous signatures of immune evasion. Using immune-competent metastasis models of LUSC developed in our lab, we have found that the CCL2-CCR2 axis is highly associated with IM recruitment and promotion of LUSC metastasis. Although studies in other cancer types have revealed IMs differentiate into tumor-associated macrophages (TAMs), which in turn leads to increased angiogenesis and invasiveness, very little is known about the direct role of IMs on LUSC growth and metastasis. Taken together, we hypothesize that specific molecular processes (i) recruit IMs into the LUSC tumor microenvironment, which (ii) directly promotes LUSC tumor growth and development of distant metastasis, and (iii) interruption of the CCL2-CCR2 axis will therapeutically inhibit these processes. In Aim 1, we will determine and characterize the upstream molecular drivers responsible for IM recruitment into the LUSC microenvironment. In Aim 2, we will determine the direct role of IMs in promoting LUSC tumor growth and metastasis. In Aim 3, we will evaluate the therapeutic efficacy of targeting IMs in immune-competent metastasis models of LUSC, and whether this therapeutic approach is synergistic in combination with anti-PD1 immune checkpoint inhibitors. Thus, taken together, our proposal aims to uncover the molecular underpinnings that promote IM infiltration into the LUSC TME, define the mechanisms by which this promotes LUSC progression, and to develop novel therapeutic strategies to interrupt these processes.

项目概要：肺癌是美国癌症相关死亡的主要原因，2015年死亡158,040人。虽然肺腺癌的靶向治疗提高了总生存率，但肺腺癌的靶向治疗也取得了类似进展。鳞状细胞癌（LUSC）的发病率一直处于停滞状态。通过癌症基因组进行广泛的分子分析 Atlas（TCGA）的研究结果显示，LUSC肿瘤具有高度特异性，很少由单独的可操作性驱动。途径。然而，肿瘤微环境（TME），促进转移，占90 癌症相关死亡的百分比，仍然是基于免疫的治疗的有吸引力的目标。近日已经证明，用抗血小板细胞死亡蛋白1（PD 1）抗体阻断免疫检查点，在LUSC患者中具有显著的治疗前景，约20%的LUSC患者经历了持久的应答因此，更全面地了解肿瘤微环境（TME）如何促进LUSC 将使我们能够在这些进步的基础上更进一步。使用LUSC更新的TCGA数据，我们发现了一个先前未鉴定的LUSC亚组，特征为炎性单核细胞（IM）浸润。这亚组占所有LUSC患者的近一半，与非常差的结局相关，并且有许多免疫逃避的特征使用我们实验室开发的LUSC免疫活性转移模型，我们我发现CCL 2-CCR 2轴与IM募集和促进LUSC高度相关转移尽管对其他癌症类型的研究已经揭示了IM分化为肿瘤相关的巨噬细胞（TAMs），这反过来又导致增加血管生成和侵袭性，知之甚少 IMs对LUSC生长和转移的直接作用。综合考虑，我们假设分子过程（i）将IM招募到LUSC肿瘤微环境中，（ii）直接促进LUSC 肿瘤生长和远处转移的发展，和（iii）CCL 2-CCR 2轴的中断将在治疗上抑制这些过程。在目标1中，我们将确定和表征上游分子负责将IM招募到LUSC微环境的驱动程序。在目标2中，我们将确定直接 IMs在促进LUSC肿瘤生长和转移中的作用。在目标3中，我们将评估治疗效果在LUSC的免疫活性转移模型中靶向IM，以及这种治疗方法是否与抗PD 1免疫检查点抑制剂组合具有协同作用。因此，综合起来，我们的建议旨在为了揭示促进IM浸润到LUSC TME中的分子基础，定义其机制从而促进LUSC进展，并开发新的治疗策略来中断这些进展。流程.