Immunology of human malignant melanoma initiating cells

描述(申请人提供)：恶性黑色素瘤起始细胞(MMIC)是少数亚群，其临床毒力是无限自我更新能力的结果，导致不可阻挡的肿瘤进展和潜在的转移。我们的实验室最近发现了人类MMIC，并显示它们表达靶向生物标记物和多药耐药转运蛋白ABCB5(《自然》杂志，2008年1月17日)。在这项研究中，证明了免疫介导的MMIC破坏的原理，并由此抑制了肿瘤的生长。最近，我们发现MMICs通过B7-2和PD1途径使用机制来抑制内源性抗肿瘤免疫(癌症研究，2010年1月15日)。这项建议寻求以翻译相关的方式进一步推进这些发现，目标是加快专门针对MMICs的抗黑色素瘤免疫疗法的临床应用进展。这项建议的具体目的是：(1)表征人类患者ABCB5+MMIC对免疫治疗的反应，并评估/预测MMIC的治疗反应；(2)在体内剖析一种新的人源化异种移植模型中抗肿瘤免疫途径与MMIC的相互作用，即黑色素瘤对Hu-PBMC nod-SCID IL2r3缺失小鼠的作用；以及(3)临床前免疫调节/MMIC靶向联合治疗。这一倡议应该会促进针对MMICs的靶向免疫疗法的快速发展和完善，从而为快速演变到临床测试提供巨大的希望。 与公共健康相关：恶性黑色素瘤是一种癌症，它的增长速度比世界上任何其他癌症都快，一旦从原发皮肤肿瘤(有时不超过一粒米)扩散到身体的重要器官，就会变得致命。到目前为止，转移性黑色素瘤还没有有效的治疗方法，这在很大程度上是因为毒性最强的黑色素瘤细胞，即癌症干细胞，对治疗具有抵抗力。我们已经成功地鉴定了这些有毒的黑色素瘤干细胞，并开发了免疫靶向和消除它们的策略，这项拨款提案将这项研究推进到了一个点，即患有其他不治之症的患者可能会显著受益。

DESCRIPTION (provided by applicant): Malignant melanoma initiating cells (MMICs) are minority subpopulations in which clinical virulence resides as a consequence of unlimited self-renewal capacity, resulting in inexorable tumor progression and potential metastasis. Our laboratories have recently identified human MMICs and shown them to express the targetable biomarker and multidrug resistance transporter, ABCB5 (Nature, Jan 17, 2008). In this study, proof of principle of immune-mediated MMIC destruction and consequent inhibition of tumor growth was demonstrated. More recently, we have shown that MMICs employ mechanisms to thwart endogenous anti-tumor immunity via the B7-2 and PD1 pathways (Cancer Res, Jan 15, 2010). This proposal seeks to further advance these findings in a translationally-relevant manner with the goal of accelerating progress toward clinical application of anti- melanoma immune therapies specifically targeting MMICs. The specific aims of this proposal are: (1) Characterization of ABCB5+ MMIC response to immunotherapy in human patients and assessment/prediction of MMIC therapeutic response; (2) In vivo dissection of antitumor immunity pathway interactions with MMIC in a novel humanized xenotransplantation model, melanoma to hu-PBMC NOD-scid IL2r3null mice; and (3) Preclinical immunomodulatory/MMIC-targeted combination therapies. This initiative should enhance the rapid development and refinement of targeted immunotherapies directed against MMICs, and thus holds great promise for rapid evolution to clinical testing. PUBLIC HEALTH RELEVANCE: Malignant melanoma, a form of cancer that is increasing faster than any other cancer worldwide, becomes deadly once it spreads from a primary skin tumor (sometimes no larger than a grain of rice) to the body's vital organs. Until now, there is no effective therapy for metastatic melanoma, in large part because the most virulent melanoma cells, called cancer stem cells, are resistant to treatment. We have successfully identified these virulent melanoma stem cells, and have developed strategies to immunologically target and eliminate them, and this grant proposal advances this research to a point whereby patients with otherwise incurable disease may significantly benefit.