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.

项目摘要：肺癌是美国与癌症有关的主要原因，2015年占158,040例死亡。虽然针对肺腺癌的靶向疗法提高了总体生存率，但肺部的进展相似鳞状癌（LUSC）停滞不前。通过癌症基因组进行广泛的分子分析 Atlas（TCGA）的努力表明，LUSC肿瘤是高度特质的，很少受到孤立驱动的驱动途径。但是，肿瘤微环境（TME），促进了占90的转移与癌症相关的死亡中的百分比仍然是免疫疗法的吸引人目标。最近，用抗编程的细胞死亡蛋白1（PD1）抗体阻断免疫检查点已证明 LUSC患者的显着治疗承诺，约有20％的未选择的患者经历耐用的患者回答。因此，对肿瘤微环境（TME）如何促进LUSC的更全面了解将允许我们以这些进步为基础。使用更新的TCGA数据for LUSC，我们发现了一个以前未鉴定的LUSC子集，其特征是炎性单核细胞（IMS）的浸润。这子集近一半的LUSC患者占一半，与结果非常差有关，并且有许多免疫逃避的签名。使用实验室中开发的LUSC的免疫能力转移模型，我们发现CCL2-CCR2轴与IM募集和促进LUSC高度相关转移。尽管其他癌症类型的研究表明IMS分化为肿瘤相关巨噬细胞（TAM）又导致血管生成和侵入性增加，鲜为人知关于IMS在LUSC生长和转移中的直接作用。综上所述，我们假设该具体分子过程（i）招募IMS进入LUSC肿瘤微环境，该环境（ii）直接促进了LUSC 远处转移的肿瘤生长和发育，（iii）CCL2-CCR2轴的中断将治疗抑制这些过程。在AIM 1中，我们将确定和表征上游分子负责IM招募到LUSC微环境的驾驶员。在AIM 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AIM 3中，我们将评估治疗功效在LUSC的免疫能力转移模型中靶向IM，以及这种治疗方法是否为结合抗PD1免疫检查点抑制剂的协同作用。因此，总之，我们的建议目标要揭示促进IM渗透到LUSC TME的分子基础，请定义机制通过这促进LUSC的进展，并制定新颖的治疗策略来中断这些过程。