Immune Regulation of Lung Squamous Metastasis

肺鳞状细胞癌的免疫调节

• 批准号: 9770826
• 负责人: Chad V Pecot
• 金额: $ 38.11万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770826
• 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; Immune Evasion; Immune Targeting; Immune checkpoint inhibitor; 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; PDCD1LG1 gene; Pathway interactions; Patients; Play; Process; Proteins; Research; Resected; Role; Sampling; Signal Transduction; Squamous Cell Lung Carcinoma; Squamous cell carcinoma; TNF gene; The Cancer Genome Atlas; Therapeutic; Tissue Microarray; Treatment Efficacy; Tumor-associated macrophages; Update; angiogenesis; cancer type; chemokine; chemotherapy; engineered T cells; experience; experimental study; immune checkpoint blockade; immunoregulation; improved; in vivo; inhibitor/antagonist; monocyte; novel; novel therapeutics; paracrine; programs; recruit; response; targeted treatment; tumor; tumor growth; tumor microenvironment

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 年肺癌死亡人数为 158,040 人。 虽然肺腺癌的靶向治疗改善了总体生存率，但肺腺癌的类似进展 鳞状癌（LUSC）的发展一直停滞不前。通过癌症基因组进行广泛的分子分析 Atlas (TCGA) 工作表明，LUSC 肿瘤具有高度特殊性，很少由单独可操作的肿瘤驱动 途径。然而，促进转移的肿瘤微环境（TME）占 90 癌症相关死亡的百分比仍然是免疫疗法的一个有吸引力的目标。最近， 已证明用抗程序性细胞死亡蛋白 1 (PD1) 抗体可阻断免疫检查点 对 LUSC 患者具有显着的治疗前景，约 20% 的未经选择的患者经历了持久的治疗 回应。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再接再厉。使用 LUSC 的更新 TCGA 数据，我们发现了 以前未识别的 LUSC 子集，其特征是炎症单核细胞 (IM) 浸润。这 该子集占所有 LUSC 患者的近一半，与非常差的结果相关，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 发现 CCL2-CCR2 轴与 IM 招募和 LUSC 促进高度相关 转移。尽管对其他癌症类型的研究表明 IM 分化为肿瘤相关的 巨噬细胞 (TAM) 反过来会导致血管生成和侵袭性增加，但人们对此知之甚少 关于 IM 对 LUSC 生长和转移的直接作用。综合起来，我们假设特定的 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，以及 (iii) CCL2-CCR2 轴的中断将 治疗性地抑制这些过程。在目标 1 中，我们将确定并表征上游分子 负责将 IM 招募到 LUSC 微环境中的驱动程序。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 LUSC 免疫活性转移模型中靶向 IM 的效果，以及这种治疗方法是否有效 与抗PD1免疫检查点抑制剂联合使用具有协同作用。因此，总的来说，我们的提案旨在 揭示促进 IM 渗透到 LUSC TME 的分子基础，定义机制 从而促进 LUSC 进展，并开发新的治疗策略来中断这些 流程。