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

描述(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30,000多例新确诊的肾癌病例，近13,000名患者死于肾癌。肾细胞癌分为三种不同的组织亚型，其中透明细胞(CcRCC)是最常见和最致命的形式，占肾癌相关死亡的近90%。大多数现在被诊断为ccRCC的患者都会出现器官受限的肿瘤，似乎可以手术切除。然而，这些患者中几乎有一半会在手术后经历转移复发。转移性肾细胞癌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然包括：1)更好的方法来识别手术后转移复发的高危患者；2)更好地了解驱动CcRCC转移进展的分子机制；以及3)合理的、机制靶向的治疗方法来治疗CcRCC患者的转移疾病。这种改善可能源于引入更新、更有效的药物或优化联合疗法。在本提案中，重点将放在后一个主题上，以更好地了解与晚期肾细胞癌的免疫生物学和免疫治疗相关的关键问题。我们最近报道，肾细胞癌可以异常表达几种较新的免疫细胞共调节配体，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的ccRCC行为，包括增加癌症进展和癌症相关死亡的风险。总而言之，这些观察结果提出了人类肿瘤可能使用B7-H配体解除宿主抗肿瘤免疫以促进恶性进展的明显可能性。因此，肿瘤相关的B7-H配体可能会被证明是有用的，以完善预后算法，以精确定位最容易发生肾细胞癌进展和死亡的高危患者。然而，肿瘤相关的B7-H配体是否真的发挥了细胞介导的抗肿瘤免疫的临床抑制作用，以促进恶性进展仍有待确定。这项建议特别致力于研究，我们相信，将直接改善临床肾细胞癌患者的护理。具体地说，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。具体地说，我们将回答一个最重要的问题：“临床肿瘤中的B7-H配体是否真的能够损害癌症患者的抗肿瘤免疫？”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)。具体目标1-4的统一假设：这一提议的总体假设是，ccRCC肿瘤的侵袭性行为至少部分源于肿瘤制定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免疫。我们进一步推测，最具侵袭性的ccRCC肿瘤同时表达增加的其他促进肿瘤细胞增殖和存活的蛋白质，也可能作为抗原部分诱使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，每个目标都解决了与B7-H配体有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。具体目的1.测试假定的免疫抑制、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，以及是否可以与其他有助于促进肿瘤细胞增殖和生存的分子标记(IMP3、CAIX、Ki-67和Survivin)合作，以改善对ccRCC患者的预后预测。具体目的2.与发生转移的患者相匹配的原发肿瘤相比，测试ccRCC转移是否富含预后B7-H相关分子(B7-H1、B7-H3、B7-H4和PD-1)以及IMP3、Ki-67和Survivin。具体目的3.检测是否可以在慢性肾细胞癌患者血清中检测到可溶性B7-H(SB7-H)配体，以改进监测和免疫治疗慢性肾细胞癌患者的策略。具体目的4.在临床肾细胞癌标本中，使用原位免疫组化分析结合免疫细胞功能的体外检测，检测肿瘤相关的B7-H配体是否抑制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.