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 通路在 R01 资助期的前五年（2014 年 4 月 – 3 月） 2019年），我们发表了37篇出版物并获得了3项授权专利。 B7x（一个研究较少的 B7 家族）功能和结构的重大发现我们最初发现的成员。 PD-1/PD-L1 和 CTLA-4 的免疫检查点阻断已取得进展然而，癌症患者的治疗面临的最大挑战之一是。显然，大多数癌症患者对这些新疗法没有反应。需要针对额外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，并提供了极好的此外，我们最近发现了开发新免疫疗法的目标。 HHLA2作为B7x的同源物，也是B7家族的新成员，它提供这是研究新的人类免疫检查点的独特机会。中心假设是 B7x 和 HHLA2，B7 中两个较少研究的成员我们最初发现的家族是体内关键的免疫逃避途径肿瘤微环境，是新癌症的治疗靶点该假设将通过追求三个目标来检验：1）剖析肿瘤表达 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 通路：B7x 的新同源性。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。该项目将揭示肿瘤中新的免疫逃避机制微环境，将为新药物的临床设计奠定基础免疫疗法，这可能对抵抗肿瘤有效目前PD-1/PD-L1和CTLA-4靶向治疗。