The B7x pathways in the tumor microenvironment

肿瘤微环境中的B7 x通路 R 01资助期的前五年（2014年4月至2015年3月） 2019年），我们发表了37篇论文，并获得了3项授权专利。我们做 关于B7 x功能和结构的重大发现，这是一个研究较少的B7家族 这是我们最初发现的。 PD-1/PD-L1和CTLA-4的免疫检查点阻断已经进展 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，新 需要针对额外的免疫检查点的策略来改善免疫系统。 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B7 x 免疫检查点具有非常不同的机制， 以开发新免疫疗法为目标。此外，我们最近发现， HHLA 2是B7 x的同系物，也是B7家族的新成员，它提供了 一个研究新的人类免疫检查点的独特机会。所以我们 中心假设是B7 X和HHLA 2，两个研究较少的B7成员 我们最初发现的家族，是体内重要的免疫逃避途径， 肿瘤微环境，是新癌症的治疗靶点 免疫疗法这一假设将通过追求三个目标来检验：1） 剖析肿瘤表达B7 x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 靶向B7 x的免疫检查点阻断：联合治疗和 阐明HLA 2通路：B7 x的一种新同源性。我们 已经产生了一些新的工具，为我们提供了独特的 应对挑战和实现目标的机会。这个结果 该项目将揭示肿瘤中新的免疫逃避机制 微环境，并将建立新的临床设计的基础 免疫疗法，这可能是有效的肿瘤， 目前的PD-1/PD-L1和CTLA-4靶向治疗。

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.