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The B7x pathways in the tumor microenvironment

肿瘤微环境中的 B7x 通路

基本信息

批准号：
10738320
负责人：
Xingxing Zang
金额：
$ 8.07万
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：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10738320
关键词：
Address Ants Award Biology Bladder CAR T cell therapy CD276 gene CD28 gene CD80 gene CTLA4 gene Cancer Patient Cell physiology Cells Clinical Clinical Research Colon Combined Modality Therapy Copy Number Polymorphism Data Esophagus Family Family member Foundations Funding Gene Dosage Goals Grant Homologous Gene Human Immune Immune Evasion Immunosuppression Immunotherapy Islet Cell Kidney Legal patent Liver Lung Transplantation Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of esophagus Malignant neoplasm of lung Malignant neoplasm of pancreas Malignant neoplasm of thyroid Mission Molecular Monoclonal Antibodies Outcome Ovary PD-1/PD-L1 Pancreas Pathway interactions Phylogenetic Analysis Prostate Proteins Public Health Publications Renal carcinoma Research Skin Structure T-Lymphocyte Testing Therapeutic Transgenic Mice Translating Treatment Efficacy Trees Tumor Immunity United States National Institutes of Health VTCN1 gene cancer immunotherapy cancer therapy clinically significant cytokine design immune checkpoint immune checkpoint blockade improved innovation insight malignant breast neoplasm melanoma member mouse model neoplastic cell new therapeutic target novel overexpression programmed cell death ligand 1 programmed cell death protein 1 programs receptor targeted treatment tool tumor tumor microenvironment tumor progression tumorigenesis

项目摘要

The B7x pathway in the tumor microenvironment During the first five years of the R01 funding period (April 2014 – March 2019), we produced 37 publications and received 3 granted patents. We made major discoveries on function and structure of B7x, a much less studied B7 family member that was originally discovered by us. Immune checkpoint blockade of PD-1/PD-L1 and CTLA-4 have advanced the treatment of cancer patients. However, one of the biggest challenges is that the majority of cancer patients do not respond to these treatments. Clearly, new strategies targeting additional immune checkpoints are needed to improve the immunotherapy of human cancers. Our basic and clinical studies and crystal structure analysis suggest B7x immune checkpoint has very different mechanisms and provides an excellent target to develop new immunotherapies. Furthermore, we recently discovered HHLA2 as a homolog of B7x and a new member of the B7 family, which provides a unique opportunity to study a new human immune checkpoint. Thus, our central hypothesis is that B7x and HHLA2, two less-studied members of the B7 family originally discovered by us, are critical immune evasion pathways within the tumor microenvironment and are therapeutic targets for new cancer immunotherapies. This hypothesis will be tested by pursuing three aims: 1) Dissect molecular and cellular mechanisms by which tumor-expressed B7x induces immunosuppression within the tumor microenvironment; 2) Develop new immune checkpoint blockade targeting B7x: Combination therapies and mechanisms; and 3) Elucidate the HHLA2 pathway: A new homology of B7x. We have generated a number of novel tools which provides us with unique opportunities to address challenges and realize goals. The outcomes of this project will reveal new immune evasion mechanisms in the tumor microenvironment and will establish the foundation for clinical design of new immunotherapies, which could potentially be effective in tumors that resist current PD-1/PD-L1 and CTLA-4 targeted therapies.

肿瘤微环境中的B7x途径在R01资助期的前五年(2014年4月至3月 2019年)，我们制作了37种出版物，获得3项授权专利。我们做了研究较少的B7家族B7x的功能和结构的主要发现最早由我们发现的成员。 PD-1/PD-L1和CTLA-4免疫检查点阻断取得进展癌症患者的治疗。然而，最大的挑战之一是，大多数癌症患者对这些治疗没有反应。显然，这是新的需要针对更多免疫检查点的策略来改善人类癌症的免疫疗法。我们的基础和临床研究以及晶体结构分析表明B7x 免疫检查点具有非常不同的机制，并提供了一种极好的目标是开发新的免疫疗法。此外，我们最近发现， HHLA2是B7x的同源物，是B7家族的新成员，它提供了这是研究一种新的人类免疫检查点的独特机会。因此，我们的中心假设是B7x和HHLA2，两个较少研究的B7成员最初由我们发现的家族，是体内关键的免疫逃避途径肿瘤微环境，是新肿瘤的治疗靶点免疫疗法。这一假设将通过追求三个目标来检验：1) 剖析肿瘤细胞表达B7x的分子和细胞机制在肿瘤微环境中诱导免疫抑制；2)开发新的针对B7x的免疫检查点阻断：联合疗法和机制；3)阐明HHLA2途径：B7x的一个新同源物。我们产生了许多新颖的工具，为我们提供了独特的应对挑战和实现目标的机会。这样做的结果是该项目将揭示肿瘤中新的免疫逃避机制微环境，将为新的临床设计奠定基础免疫疗法，这可能对抵抗的肿瘤有效目前的PD-1/PD-L1和CTLA-4靶向治疗。