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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

基本信息

批准号：
8589371
负责人：
Haidong Dong
金额：
$ 26.81万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8589371
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

项目摘要

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）涵盖 90% 的肾癌和 3% 的成人癌症。仅在美国，每年就诊断出超过 30,000 例新发 RCC 病例，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) 是最常见和最致命的形式，占 RCC 相关死亡的近 90%。现在诊断为 ccRCC 的大多数患者都会出现器官局限性肿瘤，似乎适合手术切除。然而，这些患者中几乎一半会在手术后出现转移复发。转移性 ccRCC 的治疗选择在范围和疗效方面都受到限制。因此，改善 ccRCC 患者护理的关键进展必然包括：1）更好的方法来识别术后转移复发高风险的患者； 2) 更好地了解驱动 ccRCC 转移进展的分子机制； 3）合理的、机制靶向的疗法来治疗ccRCC患者的转移性疾病。这种改进可能源于更新、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 配体的肿瘤表达增强可以预测侵袭性 ccRCC 行为，包括癌症进展和癌症相关死亡风险的增加。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 配体来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 配体可能有助于完善预后算法，以查明最容易发生 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来促进恶性进展仍有待确定。我们相信，该提案专门致力于那些将直接改善临床 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）。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的免疫。我们进一步假设，最具侵袭性的 ccRCC 肿瘤同时表达其他蛋白质水平升高，促进肿瘤细胞增殖和存活，并且也可能作为抗原部分来引诱免疫细胞进入危险的瘤内环境。因此，我们提案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 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记物（IMP3、CAIX、Ki-67 和 survivin）协作，以改善 ccRCC 患者的预后预测。具体目标 2. 测试与产生转移的患者匹配的原发肿瘤相比，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 和生存素。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 (sB7-H) 配体，以改进监测和免疫治疗 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，测试肿瘤相关 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。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A gender factor in shaping T-cell immunity to melanoma.

DOI：
10.3389/fonc.2015.00008
发表时间：
2015
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
Dronca RS;Dong H
通讯作者：
Dong H

B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis.

DOI：
10.1097/jto.0000000000000177
发表时间：
2014-07
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
0
作者：
Mansfield AS;Roden AC;Peikert T;Sheinin YM;Harrington SM;Krco CJ;Dong H;Kwon ED
通讯作者：
Kwon ED

Re: Presence of tumor necrosis is not a significant predictor of survival in clear cell renal cell carcinoma: higher prognostic accuracy of extent based rather than presence/absence classification. T. Klatte, J. W. Said, M. de Martino, J. Larochelle, B. S

回复：肿瘤坏死的存在并不是透明细胞肾细胞癌生存的重要预测因子：基于程度而不是存在/不存在分类的预后准确性更高。