Clinical Impact of B7-H Immune Cell Coregulators in Renal Cell Carcinoma

描述（由申请人提供）：肾细胞癌（RCC）包括90%的肾癌和3%的成人癌症。仅在美国，每年就有3万多例新的肾细胞癌确诊病例，近1.3万名患者死于肾细胞癌。RCC分为三种不同的组织学亚型，其中透明细胞（ccRCC）是最常见和致命的亚型，占RCC相关死亡的近90%。目前诊断为ccRCC的大多数患者将表现为器官局限性肿瘤，似乎适合手术切除。然而，几乎一半的患者在手术后会出现转移性复发。转移性ccRCC的治疗选择在范围和疗效方面都是有限的。因此，改善ccRCC患者护理的关键进展必须包括：1)更好地识别术后转移性复发高风险患者的方法；2)更好地理解驱动ccRCC转移进展的分子机制；3)合理的、机制的靶向治疗ccRCC患者的转移性疾病。这种改善可能源于更新、更有效的药物的引入或联合疗法的优化。在本提案中，重点将放在后一个主题，以更好地了解与晚期ccRCC的免疫生物学和免疫治疗相关的关键问题。我们最近报道了ccRCC肿瘤可以异常表达几种相对较新的免疫细胞协同调节配体，即B7-H1， B7-H3和B7-H4。我们进一步表明，这些B7-H配体的肿瘤表达增强可以预测侵袭性ccRCC行为，包括增加癌症进展和癌症相关死亡的风险。总的来说，这些观察结果提出了一种明显的可能性，即人类肿瘤可能利用B7-H配体解除宿主的抗肿瘤免疫，从而促进恶性进展。因此，肿瘤相关的B7-H配体可能有助于改进预后算法，以确定最容易发生ccRCC进展和死亡的高危患者。然而，肿瘤相关的B7-H配体是否真的作为细胞介导的抗肿瘤免疫的临床抑制剂来促进恶性进展仍有待确定。我们相信，这项提案特别致力于将直接改善临床ccRCC患者护理的研究。具体来说，我们的研究将严格测试ccRCC异常表达的B7-H配体的预后和免疫治疗潜力。具体来说，我们将解决一个最重要的问题：“临床肿瘤中的B7-H配体真的会损害癌症患者的抗肿瘤免疫功能吗？”这些发现将有助于确定体内B7-H配体阻断作为治疗人类恶性肿瘤的临床免疫治疗方法的优点（和局限性）。针对特定目标的统一假设1- 4：该提议的总体假设是，ccRCC肿瘤的侵袭性行为至少部分源于肿瘤精心设计一系列同源但空间分布的B7-H配体的能力，这些配体协同作用，破坏癌症患者的细胞介导免疫。我们进一步假设，最具侵袭性的ccRCC肿瘤同时表达其他促进肿瘤细胞增殖和存活的蛋白水平升高，并且也可能作为抗原片段诱导免疫细胞进入危险的肿瘤内环境。因此，我们建议的每个目标都是独立的，每个目标都解决与B7-H配体相关的关键临床和科学问题，并从宏观到微观理解B7-H配体作为临床ccRCC的免疫调节剂和免疫治疗靶点。具体目标检测推定的免疫抑制、肿瘤相关的B7-H配体（B7-H1、B7-H3、B7-H4和PD-1）是否可以相互协作，以及与其他有助于促进肿瘤细胞增殖和存活的分子标志物（IMP3、CAIX、Ki-67和survivin）协作，以改善ccRCC患者的预后预测。具体目标2。检测ccRCC转移灶是否富集与预后相关的B7-H分子（B7-H1、B7-H3、B7-H4和PD-1）以及IMP3、Ki-67和survivin，与患者匹配的转移灶原发肿瘤相比。具体目标3。检测可溶性B7-H （sB7-H）配体是否可以在ccRCC患者的血清中检测到，以改进ccRCC患者的监测策略，并可能对其进行免疫治疗。具体目标使用原位免疫组化分析结合体外免疫细胞功能测定，检测肿瘤相关B7-H配体是否抑制临床ccRCC标本中T和NK细胞介导的免疫反应。

DESCRIPTION (provided by applicant): Renal cell carcinoma (RCC) encompasses 90% of kidney cancers and 3% of adult cancers. In the U.S. alone, more than 30,000 new cases of RCC are diagnosed and nearly 13,000 patients die from RCC annually. RCC is categorized into three distinct histologic subtypes of which clear cell (ccRCC) is the most common and lethal form, accounting for nearly 90% of RCC-related deaths. The majority of patients now diagnosed with ccRCC will present with organ-confined tumors seemingly amenable to surgical extirpation. Yet, almost half of these patients will experience metastatic relapse after surgery. Treatment options for metastatic ccRCC are limited both in terms of scope and efficacy. Thus, key advances to improve ccRCC patient care will necessarily include: 1) better methods to identify patients at high risk for metastatic relapse following surgery; 2) a better understanding of molecular mechanisms that drive ccRCC metastatic progression; and 3) rational, mechanism- targeted therapies to treat metastatic disease in ccRCC patients. Such improvements could emanate from the introduction of newer, more effective drugs or optimization of combination therapies. In this proposal, emphasis will be placed on the latter topic to gain a better understanding of key issues related to the immunobiology and immunotherapeutic treatment of advanced ccRCC. We have recently reported that ccRCC tumors can aberrantly express several relatively novel immune cell coregulatory ligands, namely B7-H1, B7-H3 and B7-H4. We have further shown that enhanced tumor expression of these B7-H ligands can predict aggressive ccRCC behavior including enhanced risk for cancer progression and cancer-related death. Collectively, these observations raise the distinct possibility that human tumors might employ B7-H ligands to disarm host antitumoral immunity in order to promote malignant progression. Thus, tumor-associated B7-H ligands will likely prove useful to refine prognostic algorithms to pinpoint high-risk patients who are most prone to ccRCC progression and death. However, whether tumor- associated B7-H ligands actually function as clinical inhibitors of cell-mediated antitumoral immunity to promote malignant progression remains to be determined. This proposal is singularly devoted to studies that, we believe, will directly improve clinical ccRCC patient care. Specifically, our studies will rigorously test the prognostic and immunotherapeutic potential of B7-H ligands aberrantly expressed by ccRCC. Specifically, we will address a most vital question: "Do B7-H ligands within clinical tumors truly function to impair antitumoral immunity in cancer patients?" Such findings will help to establish the merits (and limitations) of in vivo B7-H ligand blockade as a clinical immunotherapeutic approach to treat human forms of malignancy. Unifying Hypothesis for Specific Aims 1- 4: The overall hypothesis for this proposal is that the aggressive behavior of ccRCC tumors stems, at least in part, from the ability of tumors to elaborate an array of homologous but spatially distributed B7-H ligands that act in concert to undermine cell-mediated immunity in cancer patients. We further postulate that the most aggressive of ccRCC tumors concurrently express increased levels of other proteins that promote tumor cell proliferation and survival and, may also serve as antigenic moieties to lure immune cells into a perilous intratumoral environment. Thus, each aim of our proposal has been crafted to be free-standing, each addressing key clinical and scientific issues pertaining to B7-H ligands and moving from a macroscopic to microscopic understanding of B7-H ligands as immune- regulators and immunotherapeutic targets for clinical ccRCC. Specific Aim 1. Test if putative immunosuppressive, tumor-associated B7-H ligands (B7-H1, B7-H3, B7-H4, and PD-1) can collaborate with each other, as well as with other molecular markers that assist in fostering tumor cell proliferation and survival (IMP3, CAIX, Ki-67, and survivin) to improve outcome prediction for ccRCC patients. Specific Aim 2. Test whether ccRCC metastases are enriched for prognostic B7-H related molecules (B7-H1, B7-H3, B7-H4, and PD-1) as well as IMP3, Ki-67, and survivin when compared against patient-matched primary tumors from which metastases arise. Specific Aim 3. Test if soluble B7-H (sB7-H) ligands can be detected in the sera of ccRCC patients to improve strategies to monitor and, perhaps, immunotherapeutically treat ccRCC patients. Specific Aim 4. Test if tumor-associated B7-H ligands inhibit T and NK cell-mediated immune responses within clinical ccRCC specimens using in situ IHC analysis in combination with in vitro assays of immune cell function.