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

B7-H 免疫细胞共调节剂对肾细胞癌的临床影响

• 批准号: 8215908
• 负责人: Haidong Dong
• 金额: $ 30.41万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215908
• 关键词: Accounting; Address; Adult; Affect; Aggressive behavior; Algorithms; Antibodies; Antigens; Area; Automobile Driving; Basic Science; Behavior; Biological Response Modifiers; Cancer Patient; Cancer Relapse; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cellular Immunity; Cessation of life; Clear Cell; Clinical; Clinical Sciences; Clinical Trials; Combined Modality Therapy; Diagnosis; Disease; Disease Progression; Employee Strikes; Environment; Excision; Fostering; Generations; Health; Histologic; Human; Immune; Immune Targeting; Immune response; Immunity; Immunobiology; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; In Situ; Injury; Intervention; Kidney; Ligands; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Mediating; Metastatic Renal Cell Cancer; Methods; Microscopic; Modeling; Molecular; Monitor; Morbidity - disease rate; Natural Killer Cells; Neoplasm Metastasis; Operative Surgical Procedures; Organ; Outcome; Patient Care; Patient Monitoring; Patient-Centered Care; Patients; Pharmaceutical Preparations; Plant Roots; Primary Neoplasm; Proteins; Recurrent Malignant Neoplasm; Refractory; Regulation; Relapse; Renal Cell Carcinoma; Renal carcinoma; Reporting; Residual Cancers; Risk; Serum; Specificity; Specimen; Stratification; Survival Rate; T-Lymphocyte; Testing; Translating; base; cancer risk; cell mediated immune response; clinically relevant; experience; high risk; immunogenic; immunogenicity; improved; in vitro Assay; in vivo; inhibitor/antagonist; injured; insight; killings; molecular marker; neoplastic cell; novel; outcome forecast; prognostic; stem; survivin; tool; tumor; tumor progression

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.

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，每年就有超过30，000例新的RCC病例被诊断出来，近13，000名患者死于RCC。RCC分为三种不同的组织学亚型，其中透明细胞（ccRCC）是最常见和致命的形式，占RCC相关死亡的近90%。现在诊断为ccRCC的大多数患者将出现器官局限性肿瘤，似乎适合手术切除。然而，这些患者中几乎有一半在手术后会发生转移性复发。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将必然包括：1）更好的方法来识别手术后转移复发的高风险患者; 2）更好地理解驱动ccRCC转移进展的分子机制;以及3）合理的机制靶向疗法来治疗ccRCC患者的转移性疾病。这种改善可能源于引进更新、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新颖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配体的增强的肿瘤表达可以预测侵袭性ccRCC行为，包括癌症进展和癌症相关死亡的风险增加。总的来说，这些观察结果提出了人类肿瘤可能利用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B7-H配体可能被证明可用于改进预后算法，以确定最容易发生ccRCC进展和死亡的高风险患者。然而，肿瘤相关的B7-H配体是否实际上作为细胞介导的抗肿瘤免疫的临床抑制剂起作用以促进恶性进展仍有待确定。我们认为，这项提案专门用于直接改善临床ccRCC患者护理的研究。具体而言，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配体真的能损害癌症患者的抗肿瘤免疫吗？“这些发现将有助于建立体内B7-H配体阻断作为治疗人类恶性肿瘤的临床免疫方法的优点（和局限性）。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能够精心制作一系列同源但空间分布的B7-H配体，这些配体共同作用以破坏癌症患者的细胞介导的免疫。我们进一步假设，最具侵袭性的ccRCC肿瘤同时表达促进肿瘤细胞增殖和存活的其他蛋白质的水平增加，并且还可以作为抗原部分将免疫细胞引诱到危险的瘤内环境中。因此，我们提案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，并从宏观到微观地理解B7-H配体作为临床ccRCC的免疫调节剂和免疫调节靶标。具体目标1.测试假定的免疫抑制性肿瘤相关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（IMP 3、CAIX、Ki-67和生存素）协作，以改善ccRCC患者的结局预测。具体目标2。检测ccRCC转移灶是否富含预后性B7-H相关分子（B7-H1、B7-H3、B7-H4和PD-1）以及IMP 3、Ki-67和生存素，与发生转移灶的患者匹配原发性肿瘤进行比较。具体目标3。测试是否可以在ccRCC患者的血清中检测到可溶性B7-H（sB 7-H）配体，以改善监测和免疫治疗ccRCC患者的策略。具体目标4。使用原位IHC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细胞介导的免疫应答。