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

• 批准号: 8125024
• 负责人: JENNIFER D WU
• 金额: $ 35.32万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-11 至 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8125024
• 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; public health relevance; receptor; therapeutic target; treatment strategy; tumor; tumor progression; tumorigenesis

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. PUBLIC HEALTH RELEVANCE: Targeting MIC shedding to revive host NKG2D-mediated immune response in prostate cancer 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 our identified shedding-motif is a therapeutic target and to evaluate the preventive and therapeutic impacts of targeting MIC shedding with our novel antibody in combination with amplification of NKG2D-mediated immune response by the IL-15 agonist. The proposed study will elucidate the mechanisms of targeting MIC shedding and the MIC-NKG2D-based dynamic interaction of tumor cells with the immune systems. Moreover, this proposed study will validate the effectiveness our novel antibody for prostate cancer prevention and therapy using our generated novel double transgenic animal models. Furthermore, as shedding of MIC was evident in many malignancies, the outcomes of this proposed research will have broad clinical implications for epithelial cancer therapy.

描述（由申请人提供）：在前列腺癌中靶向MIC脱落以恢复宿主NKG2D介导的免疫反应NKG2D介导的肿瘤排斥已在实验动物模型中得到充分证明。在人类中，由于人类 NKG2D 配体、MHC I 类链相关分子家族 MICA 和 MICB（统称为 MIC）的肿瘤脱落，该系统无效。强有力的证据表明，肿瘤脱落的 MIC 会对 NKG2D 介导的免疫产生多重负面影响，并表明这是肿瘤逃避免疫破坏和进展的机制之一。尽管多种酶已被证明参与其中，但肿瘤释放 MIC 的机制尚不完全清楚。然而，这些酶的功能复杂性可能使得使用抑制剂来靶向 MIC 脱落来进行癌症治疗在临床上不可行。我们的长期目标是确定抑制 MIC 脱落的最佳策略，并最终利用 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。在我们完成的研究中，我们已经证明，防止 MIC 脱落会导致体内前列腺肿瘤排斥。最近，我们在 MIC 的 a3 结构域中定义了一个对于调节 MIC 脱落至关重要的 11-aa 基序（脱落基序），并生成了一种单链抗体 (scFv)，它通过靶向脱落基序来抑制 MIC 脱落。在这项提议中，我们特别假设，针对 MIC 脱落与 IL-15 激动剂放大 NKG2D 介导的免疫反应相关，可以减缓前列腺癌的进展。该提案的实验重点是引出 11-aa 脱落基序作为治疗靶点的机制，并评估使用我们的新型抗体靶向 MIC 脱落与 NKG2D 介导的免疫反应放大相关的治疗效果。我们的具体目标是： 1) 阐明脱落基序调节 MIC 脱落的机制，并作为抑制 MIC 脱落的治疗靶点； 2) 确定持续的肿瘤细胞表面 MIC 刺激对 NK 细胞中 NKG2D 功能的影响以及 IL-15 激动剂在这方面的影响； 3) 评估抗体介导的MIC脱落抑制联合IL-15激动剂对前列腺肿瘤发生和进展的治疗影响。如果我们证明用我们的抗体与 IL-15 激动剂组合抑制 MIC 脱落可以在动物模型中成功利用宿主抗肿瘤免疫反应，那么该治疗策略可以很容易地转化为前列腺癌的临床试验。此外，该试剂还可以进一步设计用于临床应用。此外，由于许多恶性肿瘤中都有明显的 MIC 脱落，因此这项研究的结果将对癌症治疗产生广泛的临床影响。 公共健康相关性：针对 MIC 脱落以恢复前列腺癌中宿主 NKG2D 介导的免疫反应在本提案中，我们特别假设，针对 MIC 脱落与 IL-15 激动剂放大 NKG2D 介导的免疫反应相关，可以减弱前列腺癌的进展。该提案的实验重点是引出我们确定的脱落基序作为治疗靶标的机制，并评估使用我们的新型抗体靶向 MIC 脱落并结合 IL 放大 NKG2D 介导的免疫反应的预防和治疗效果-15激动剂。拟议的研究将阐明靶向 MIC 脱落的机制以及肿瘤细胞与免疫系统基于 MIC-NKG2D 的动态相互作用。此外，这项拟议的研究将使用我们生成的新型双转基因动物模型来验证我们的新型抗体对于前列腺癌预防和治疗的有效性。此外，由于 MIC 脱落在许多恶性肿瘤中很明显，因此这项拟议研究的结果将对上皮癌治疗具有广泛的临床意义。