Immune Regulation of Lung Squamous Metastasis

肺鳞状细胞癌的免疫调节

• 批准号: 9445530
• 负责人: Chad V Pecot
• 金额: $ 40.06万
• 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/9445530
• 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; Engineering; Epigenetic Process; Fibrin; Genes; Growth; Growth and Development function; Immune; Immune Evasion; Immune Targeting; Immune checkpoint inhibitor; Immunologics; Immunosuppression; Infiltration; Inflammation Mediators; Inflammatory; Interruption; Lead; 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; Recruitment Activity; Research; Resected; Role; Sampling; Signal Transduction; Squamous Cell Lung Carcinoma; Squamous cell carcinoma; T-Lymphocyte; TNF gene; The Cancer Genome Atlas; Therapeutic; Tissue Microarray; Treatment Efficacy; Update; angiogenesis; base; cancer type; chemokine; chemotherapy; experience; experimental study; immune checkpoint blockade; immunoregulation; improved; in vivo; inhibitor/antagonist; macrophage; monocyte; novel; novel therapeutics; paracrine; programs; 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.

项目总结： 肺癌是美国癌症相关死亡的主要原因，2015年有158,040人死于肺癌。 虽然肺腺癌的靶向治疗提高了总体生存率，但在肺腺癌方面也取得了类似的进展 鳞癌(LUSC)一直停滞不前。通过癌症基因组进行广泛的分子分析 Atlas(TCGA)的研究表明，LUSC肿瘤具有很高的特异性，很少由可操作的孤立肿瘤驱动 小路。然而，肿瘤微环境(TME)中，促进转移的占90% 在与癌症相关的死亡中，仍然是基于免疫的治疗的一个有吸引力的靶点。最近， 用抗程序化细胞死亡蛋白1(PD1)抗体阻断免疫检查点已经证明 在LUSC患者中有显著的治疗前景，约20%的未选定患者经历耐久 回应。因此，对肿瘤微环境(TME)如何促进LUSC有更全面的了解 将使我们能够在这些进展的基础上再接再厉。使用LUSC的更新TCGA数据，我们发现了一个 以炎性单核细胞(IMS)浸润为特征的LUSC亚群以前不明。这 亚集占所有LUSC患者的近一半，与非常差的预后相关，并有大量 这是免疫逃避的特征。利用本实验室建立的LUSC免疫活性转移模型， 我发现CCL2-CCR2轴与LUSC的IM招募和晋升高度相关 转移。尽管对其他癌症类型的研究表明，IMS分化为与肿瘤相关的 巨噬细胞(TAMs)，进而导致血管生成和侵袭性增加，人们知之甚少 关于IMS在LUSC生长和转移中的直接作用。综上所述，我们假设 分子过程(I)将IMS招募到LUSC肿瘤微环境中，(Ii)直接促进LUSC 肿瘤的生长和发展的远处转移，以及(Iii)CCL2-CCR2轴的中断将 从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微环境的司机。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。 靶向IMS在LUSC免疫活性转移模型中的作用，以及这种治疗方法是否 与抗PD1免疫检查点抑制剂联合使用具有协同作用。因此，总而言之，我们的建议旨在 为了揭示促进IM渗透到LUSC TME的分子基础，定义了机制 从而促进LUSC的进展，并开发新的治疗策略来中断这些 流程。