Immunology of human malignant melanoma initiating cells

描述（由申请人提供）：恶性黑色素瘤起始细胞（mmic）是少数亚群，其临床毒力存在于无限自我更新能力中，导致不可避免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，并证明它们表达可靶向的生物标志物和多药耐药转运体ABCB5 （Nature， 2008年1月17日）。在这项研究中，证明了免疫介导的MMIC破坏和随之而来的肿瘤生长抑制的原理。最近，我们发现mmic通过B7-2和PD1途径抑制内源性抗肿瘤免疫（Cancer Res， 2010年1月15日）。本提案旨在以翻译相关的方式进一步推进这些发现，目标是加速针对mmic的抗黑色素瘤免疫疗法的临床应用进展。本提案的具体目的是：(1)表征人类患者对免疫治疗的ABCB5+ MMIC反应并评估/预测MMIC治疗反应；(2)在一种新的人源化异种移植模型——黑色素瘤- pbmc NOD-scid il2r3缺失小鼠中，体内解剖抗肿瘤免疫途径与MMIC的相互作用；(3)临床前免疫调节/ mmic靶向联合治疗。这一举措将促进针对mmic的靶向免疫疗法的快速发展和完善，从而为快速发展到临床试验提供了巨大的希望。

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.