microRNA as biomarkers for the response to immunotherapy in melanoma

描述（由申请人提供）：恶性黑色素瘤（MM）是最具侵袭性的人类癌症之一，对常规化疗和放疗具有相对的耐药性；只有一小部分患者对免疫治疗表现出持久的反应。因此，迫切需要一种个性化的策略来开发检测方法，以指导个体患者选择适当的治疗方法。发现免疫治疗反应的预测性生物标志物是实现这一目标的重要策略，这一点在本RFA的“挑衅性问题”中有所阐述。MicroRNAs （miRNA）是调节基因表达的小的非编码rna。在多种类型的癌症中发现肿瘤细胞中miRNA表达的改变，并有助于某些癌症的治疗耐药。我们最近发现mirna参与免疫细胞的发育和功能，MM患者的无细胞血清中含有MM特异性mirna，可作为MM早期诊断和预后的生物标志物。这个应用程序的目的是测试不同的miRNA表达谱可以被检测到的假设，无论是在MM肿瘤或治疗靶向T细胞，谁是应答和谁是抵抗免疫治疗的患者之间。这些差异可以在血清中反映出来，它可以作为预测免疫治疗反应的方便、无创的生物标志物。我们将首先使用TaqMan TR-PCR阵列识别治疗反应性和治疗耐药患者之间的肿瘤特异性（Aim 1）和T细胞特异性（Aim 2） miRNA表达谱；然后确定血清特异性mirna。这些开创性研究的结果可能使我们能够预测MM患者对免疫治疗的反应，使用组织/血清mirna作为生物标志物，也可能促进新的干预策略的发展，以增加MM的免疫治疗。

DESCRIPTION (provided by applicant): Malignant melanoma (MM) is one of the most invasive human cancers with its relative resistance to conventional chemotherapy and radiotherapy; only a small percentage of patients demonstrated durable responses to immunotherapy. Thus, a personalized strategy is urgently needed to develop assays which may guide the individual patient in the selection of appropriate therapy. Discovery of predictive biomarkers for immunotherapy response is an important strategy to attain this objective, which is stated in "Provocative Questions" for this RFA. MicroRNAs (miRNA) are small non-coding RNAs which regulate gene expression. Altered miRNA expression in tumor cells are found in variety types of cancer and contribute to therapy resistance in some cancer. We recently found that miRNAs are involved in immune cell development and function, and that cell-free serum from MM patients contains MM-specific miRNAs, which may serve as biomarkers for MM early diagnosis and prognosis. This application is designed to test the hypothesis that different miRNA expression profiles can be detected, either in MM tumor or in therapeutic targeting T cells, between patients who are responsive and who are resistant to immunotherapy. These differences could be reflected in the serum, which can potentially serve as convenient, noninvasive biomarkers for prediction of response to immunotherapy. We will begin by identifying the tumor-specific (Aim 1) and T cell-specific (Aim 2) miRNA expression profiles between therapy-responsive and therapy-resistant patients using TaqMan TR-PCR arrays; then will define serum specific miRNAs. The results from the proposed pioneering studies may enable us to predict MM patients who will respond to immunotherapy, using tissue/serum miRNAs as biomarkers, and may also facilitate the development of new intervention strategies for increasing immunotherapy for MM. PUBLIC HEALTH RELEVANCE: Malignant melanoma (MM) is one of the most invasive human cancers with high potential for metastasis. The management of MM has been challenging due to its relative resistance to conventional therapy and immunotherapy. Discovery of predictive biomarkers for immunotherapy response is an important strategy to guide the individual patient in the selection of appropriate therapy, which is stated in "Provocative Questions" of this RFA. MicroRNAs (miRNA), small non-coding RNAs which regulate gene expressions, are involved in cancer development. This application is designed to identify specific miRNAs in MM tumor, therapeutic targeting T cells, and the serum as biomarkers for prediction of response to immunotherapy. The results from the proposed studies may enable us to predict MM patients who will respond to immunotherapy, and may also facilitate the development of new intervention strategies for increasing immunotherapy for MM.