B7x in Cancer: Mechanisms and Therapies

B7x 在癌症中的作用：机制和疗法

基本信息

批准号：
10084280
负责人：
Peter John
金额：
$ 5.1万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-22 至 2023-02-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084280
关键词：
Address Aftercare Binding Brain Breast CD276 gene CD28 gene CD80 gene CTLA4 gene Cancer Model Cause of Death Cell Line Cell physiology Cells Cessation of life Clinic Clinical Colon Carcinoma Combined Modality Therapy Data Development Disease Drug Targeting Effector Cell Esophagus Experimental Models FDA approved Family Generations Goals HIF1A gene Human Human Cloning Hypoxia Immune Immune Evasion Immune checkpoint inhibitor Immune system Immunity Immunologic Memory Immunologic Surveillance Immunotherapeutic agent Immunotherapy In Vitro Incubated Infiltration Kidney Ligands Lung Lymphocyte Malignant Neoplasms Mediating Metastatic Neoplasm to the Lung Modeling Monoclonal Antibodies Mus Myeloid-derived suppressor cells Neoplasm Metastasis Outcome Ovary PD-1/PD-L1 Pancreas Pathway interactions Patients Play Population Production Prostate Recurrence Regulation Role Signal Pathway Signal Transduction Skin T cell response T memory cell T-Cell Proliferation T-Lymphocyte Testing Therapeutic Therapeutic Intervention Treatment Efficacy Tumor Immunity Tumor stage Tumor-infiltrating immune cells United States VTCN1 gene Work advanced disease anti-CTLA-4 therapy anti-CTLA4 anti-PD-1 anti-PD1 therapy anti-cancer therapeutic anti-tumor immune response antigen-specific T cells base cancer cell cancer immunotherapy cancer therapy clinically relevant cytokine efficacy testing immune checkpoint in vivo in vivo Model member mouse model mutant mouse model new therapeutic target overexpression prevent programmed cell death ligand 1 programmed cell death protein 1 receptor targeted treatment therapeutic evaluation tumor tumor microenvironment tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Cancer is the second-leading cause of death in the United States, causing nearly 600,000 deaths each year. A critical aspect of cancer progression is evasion of the immune system. The B7 and CD28 families of ligands and receptors mediate essential costimulatory or coinhibitory pathways; pathways that promote or suppress the immune system, respectively. B7x (B7-H4, B7S1 or VTCN1) is a newly discovered member of the B7-family that inhibits T-cell proliferation and effector functions. It is frequently overexpressed in a wide variety of human cancers, and is generally correlated with advanced disease status and poorer clinical outcomes. Previously, we demonstrated in a mouse model that B7x promotes tumor metastasis and promotes immunosuppressive cell populations such as myeloid-derived suppressor cells (MDSCs). Further, we also showed that blockade of B7x reduces tumor metastasis, alters the tumor-infiltrating immune population to favor anti-tumor effector cells, and confers long-term immunity against tumor rechallenge. Thus, we propose two aims: (1) Elucidate the regulation and function of B7x and its role in tumor progression (2) Develop and characterize anti-B7x therapy and its effect on tumor-infiltrating immune cells. For our first aim, we will explore tumor-associated hypoxia as a mechanism for B7x expression. Further, we will characterize the effects B7x has on the survival and generation of MDSCs. Lastly, we will investigate the role of B7x in tumor development and progression in vivo by generating a mouse spontaneous cancer model. In our second aim, we will develop and characterize B7x-targeted therapy. First, we have generated several clones of human B7x-specific monoclonal antibodies, which we will test for efficacy with our experimental metastasis model in vivo. Next, in context of the long-term anti-tumor immunity conferred by anti-B7x therapy, we will investigate how B7x blockade alters memory T-cell populations. Lastly, we will test B7x blockade in combination with established checkpoint inhibitors and determine if combination therapy has synergistic effects. With these studies, we seek to gain a better understanding of the functional contribution of B7x to tumor progression, and establish it as a prime target for immunotherapy.

项目概要癌症是美国第二大死因，每年导致近 60 万人死亡年。癌症进展的一个关键方面是逃避免疫系统。 B7 和 CD28 家族配体和受体介导重要的共刺激或共抑制途径；促进或促进的途径分别抑制免疫系统。 B7x（B7-H4、B7S1 或 VTCN1）是新发现的成员 B7 家族抑制 T 细胞增殖和效应功能。它经常在广泛的范围内过度表达多种人类癌症，通常与晚期疾病状态和较差的临床症状相关结果。此前，我们在小鼠模型中证明了B7x促进肿瘤转移并促进免疫抑制细胞群，例如骨髓源性抑制细胞（MDSC）。此外，我们还研究表明，阻断 B7x 可减少肿瘤转移，改变肿瘤浸润免疫群体以利于抗肿瘤效应细胞，并赋予针对肿瘤再攻击的长期免疫力。因此，我们提出两个目标： (1) 阐明 B7x 的调节和功能及其在肿瘤进展中的作用 (2) 开发和描述抗 B7x 疗法及其对肿瘤浸润免疫细胞的影响。为了我们的第一个目标，我们将探索肿瘤相关缺氧是 B7x 表达的机制。此外，我们将描述 B7x 的效果对 MDSC 的存活和生成具有影响。最后，我们将研究 B7x 在肿瘤发展中的作用通过生成小鼠自发性癌症模型来进行体内进展。在我们的第二个目标中，我们将发展并描述 B7x 靶向治疗的特征。首先，我们生成了几个人类 B7x 特异性克隆单克隆抗体，我们将在体内实验转移模型中测试其功效。接下来，在在抗 B7x 疗法赋予长期抗肿瘤免疫力的背景下，我们将研究 B7x 如何封锁会改变记忆 T 细胞群。最后，我们将结合已建立的 B7x 封锁测试检查点抑制剂并确定联合治疗是否具有协同作用。通过这些研究，我们寻求更好地了解 B7x 对肿瘤进展的功能贡献，并将其确立为免疫治疗的主要靶点。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The B7x Immune Checkpoint Pathway: From Discovery to Clinical Trial.

B7x 免疫检查点途径：从发现到临床试验。

DOI：
10.1016/j.tips.2019.09.008
发表时间：
2019-11-01
期刊：
Trends in pharmacological sciences
影响因子：
13.8
作者：
P. John;Yao Wei;Weifeng Liu;M. Du;F. Guan;X. Zang
通讯作者：
X. Zang

The immune checkpoint B7x expands tumor-infiltrating Tregs and promotes resistance to anti-CTLA-4 therapy.

免疫检查点 B7x 会扩大肿瘤浸润性 Tregs 并促进对抗 CTLA-4 疗法的抵抗。

DOI：
发表时间：
2022-05-06
期刊：
影响因子：
16.6
作者：
John, Peter;Pulanco, Marc C;Galbo Jr, Phillip M;Wei, Yao;Ohaegbulam, Kim C;Zheng, Deyou;Zang, Xingxing
通讯作者：
Zang, Xingxing

The expanding repertoire of targets for immune checkpoint inhibition in bladder cancer: What lies beneath the tip of the iceberg, PD-L1.

膀胱癌免疫检查点抑制靶标的不断扩大：PD-L1 的冰山一角。