Targeting MIC shedding to revive host NKG2D-mediated immune response in prostate

靶向 MIC 脱落以恢复前列腺中宿主 NKG2D 介导的免疫反应

基本信息

批准号：
8607907
负责人：
JENNIFER D WU
金额：
$ 32.4万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-11 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607907
关键词：
Adenocarcinoma Agonist Amino Acid Motifs Amino Acids Animal Model Antibodies Attenuated Cancer Patient Cell surface Cells Clinical Clinical Research Clinical Trials Disease Down-Regulation Effectiveness Engineering Enzymes Epithelial Experimental Animal Model Family Frequencies Goals Human Immune response Immune system Immunity Impairment Interleukin-15 Isomerase Lead Ligands MHC Class I Genes Malignant Neoplasms Malignant neoplasm of prostate Mediating Mus Natural Killer Cells Neoplasm Metastasis Outcome Preventive Prostate Prostate Cancer therapy Prostate carcinoma Prostatic Neoplasms Reagent Research Serum Signal Transduction Staging System T-Cell Proliferation T-Lymphocyte Therapeutic Time Transgenic Animals Transgenic Mice Transgenic Organisms Translating Tumor Escape Tumor Immunity Work base cancer therapy clinical application cytokine extracellular in vivo inhibitor/antagonist mouse model neoplastic cell novel prevent prostate cancer prevention prostate carcinogenesis public health relevance receptor therapeutic target treatment strategy tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Targeting MIC Shedding to Revive Host NKG2D-mediated Immune Response in Prostate Cancer NKG2D-mediated tumor rejection has been well demonstrated in experimental animal models. In humans, the system is not effective due to tumor shedding of the human NKG2D ligands, the MHC class I chain-related family of molecules MICA and MICB (collectively termed MIC). Strong evidence has demonstrated that tumor shedding of MIC results in multiple negative effects on NKG2D-mediated immunity and suggested that it is one of the mechanisms by which tumors escape immune destruction and progress. The mechanisms by which tumors shed MIC are not fully understood, although a diverse group of enzymes have been shown to be involved. However, the functional complexity of these enzymes may not make it clinically feasible to use inhibitors to target MIC shedding for cancer therapy. Our long-term goal is to define optimal strategies to inhibit MIC shedding and ultimately to harness NKG2D-mediated anti-tumor immunity as potential therapies for prostate cancer and other MIC-positive tumors as well. In our accomplished studies, we have shown that preventing MIC shedding resulted in prostate tumor rejection in vivo. Recently we have defined an 11-aa motif (shedding motif) in the a3 domain of MIC that is critical for regulating MIC shedding and generated a single chain antibody (scFv) that inhibits MIC shedding by targeting the shedding-motif. In this proposal, we specifically hypothesize that targeting MIC shedding in association with amplification of NKG2D- mediated immune responses by IL-15 agonists can attenuate prostate cancer progression. The experimental focus of proposal is to elicit the mechanisms by which the 11-aa shedding-motif is a therapeutic target and to evaluate the therapeutic impacts of targeting MIC shedding with our novel antibody in association with amplification of NKG2D-mediated immune response. Our specific Aims are: 1) to elucidate the mechanisms by which the shedding-motif regulating MIC shedding and is a therapeutic target to inhibit MIC shedding; 2) to define the impact of persistent tumor cell surface MIC stimulation on NKG2D function in NK cells and the impact of IL-15 agonist in this context; 3) To evaluate the therapeutic impact of antibody-mediated inhibition of MIC shedding combined with IL-15 agonists in prostate tumorigenesis and progression. If we show that inhibiting MIC shedding with our antibody in combination of IL-15 agonist can successfully harness host anti- tumor immune responses in animal models, the treatment strategy can be readily translated into clinical trials for prostate cancer. In addition, the reagents can be further engineered for the clinical application. Furthermore, as shedding of MIC was evident in many malignancies, the outcomes of this proposed research will have broad clinical implications for cancer therapy.

描述（由申请人提供）：靶向麦克风脱落以恢复前列腺癌NKG2D介导的肿瘤排斥反应的宿主NKG2D介导的免疫反应，在实验动物模型中已得到很好的证明。在人类中，由于人类NKG2D配体的肿瘤脱落，MHC I链I类相关的分子云母和MICB（统称为MIC），该系统无效。有力的证据表明，MIC的肿瘤脱落会对NKG2D介导的免疫产生多种负面影响，并表明它是肿瘤逃避免疫破坏和进展的机制之一。尽管已证明涉及多样的酶，但肿瘤脱落MIC的机制尚未完全了解。但是，这些酶的功能复杂性可能无法使使用抑制剂靶向麦克风脱落进行癌症治疗。我们的长期目标是定义抑制MIC脱落的最佳策略，并最终将NKG2D介导的抗肿瘤免疫作为前列腺癌和其他MIC阳性肿瘤的潜在疗法。在我们丰富的研究中，我们表明，防止MIC脱落会导致体内前列腺肿瘤排斥。最近，我们定义了MIC A3结构域中的11-AA基序（脱落基序），这对于调节MIC脱落至关重要，并生成单链抗体（SCFV），该抗体（SCFV）通过靶向脱落的moTIF来抑制MIC脱落。在此提案中，我们特别假设靶向靶标与IL-15激动剂扩增NKG2D介导的免疫反应可以减弱前列腺癌的进展。提案的实验重点是引起11-AA脱落含量是一种治疗靶标的机制，并评估使用我们的新型抗体靶向MIC脱落的治疗影响，并与NKG2D介导的免疫反应扩增。我们的具体目的是：1）阐明调节麦克风脱落的机制，并且是抑制麦克风脱落的治疗靶标的机制； 2）在这种情况下，定义了持续的肿瘤细胞表面MIC刺激对NKG2D功能的影响以及IL-15激动剂的影响； 3）评估抗体介导的抑制MIC脱落的治疗影响，并在前列腺肿瘤发生和进展中结合IL-15激动剂。如果我们表明在IL-15激动剂组合中抑制抗体抑制MIC脱落可以成功利用动物模型中的抗肿瘤免疫反应，那么治疗策略就可以很容易地转化为前列腺癌的临床试验。此外，可以为临床应用进行进一步设计试剂。此外，由于许多恶性肿瘤在许多恶性肿瘤中都显而易见，因此这项拟议的研究的结果将对癌症治疗具有广泛的临床意义。