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

描述（由申请方提供）：靶向MIC脱落以恢复前列腺癌中宿主NKG 2D介导的免疫应答 NKG 2D介导的肿瘤排斥反应已在实验动物模型中得到充分证实。在人体中，由于人NKG 2D配体（MHC I类链相关分子家族云母和MICB（统称为MIC））的肿瘤脱落，该系统无效。强有力的证据表明，MIC的肿瘤脱落对NKG 2D介导的免疫力产生多种负面影响，并表明这是肿瘤逃避免疫破坏和进展的机制之一。肿瘤脱落MIC的机制尚未完全了解，尽管已显示涉及多种酶。然而，这些酶的功能复杂性可能使得使用抑制剂靶向MIC脱落用于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NKG 2D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，我们已经表明，防止MIC脱落导致体内前列腺肿瘤排斥。最近，我们在MIC的α 3结构域中定义了一个11-aa基序（脱落基序），该基序对于调节MIC脱落至关重要，并产生了通过靶向脱落基序来抑制MIC脱落的单链抗体（scFv）。在本提案中，我们特别假设靶向MIC脱落与IL-15激动剂扩增NKG 2D介导的免疫应答相关，可减缓前列腺癌进展。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，并评估我们的新型抗体靶向MIC脱落与NKG 2D介导的免疫应答扩增相关的治疗影响。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）确定持续肿瘤细胞表面MIC刺激对NK细胞中NKG 2D功能的影响以及IL-15激动剂在此背景下的影响; 3）评价抗体介导的MIC脱落抑制联合IL-15激动剂在前列腺肿瘤发生和进展中的治疗作用。如果我们证明用我们的抗体与IL-15激动剂的组合抑制MIC脱落可以在动物模型中成功地利用宿主抗肿瘤免疫应答，则治疗策略可以容易地转化为前列腺癌的临床试验。此外，试剂可以进一步工程化以用于临床应用。此外，由于MIC的脱落在许多恶性肿瘤中是明显的，因此这项拟议研究的结果将对癌症治疗具有广泛的临床意义。 公共卫生相关性：靶向MIC脱落以恢复前列腺癌中宿主NKG 2D介导的免疫应答在该提案中，我们特别假设靶向MIC脱落与IL-15激动剂扩增NKG 2D介导的免疫应答相关，可以减缓前列腺癌进展。该提案的实验重点是引出我们鉴定的脱落基序作为治疗靶点的机制，并评价用我们的新型抗体靶向MIC脱落与IL-15激动剂扩增NKG 2D介导的免疫应答的组合的预防和治疗影响。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-NKG 2D的动态相互作用。此外，这项拟议的研究将使用我们产生的新型双转基因动物模型验证我们的新型抗体用于前列腺癌预防和治疗的有效性。此外，由于MIC的脱落在许多恶性肿瘤中是明显的，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。

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.