Countering immune resistance in the melanoma tumor microenvironment

描述(由申请人提供)：最近的观察表明，黑色素瘤肿瘤微环境的特征可能决定了成功产生的抗肿瘤T细胞反应是否发生了肿瘤退化对耐药性的反应。我们对晚期疾病患者黑色素瘤微环境的初步基因表达谱数据表明，下游缺陷有两类：未能将激活的T细胞招募到转移部位，以及确实招募了T细胞的肿瘤微环境中存在免疫抑制机制。T细胞的转运与肿瘤部位特异性趋化因子的表达有关。已知的免疫耐药机制包括肿瘤细胞自身表达抑制配体PD-L1，FoxP3+调节性T细胞的存在，树突状细胞和内皮细胞表达的色氨酸分解酶IDO，以及APC群体低表达B7的无能促进条件。另一项观察将黑色素瘤中高水平的Notch信号与免疫治疗的抵抗和T细胞再生不良联系在一起，从而在肿瘤细胞生物学和周围微环境特征的建立之间提供了潜在的联系。这些观察已具体化为以下特定目的：1.在小鼠临床前模型中检测PD-1、调节性T细胞、IDO和无能在限制免疫介导的肿瘤消退中的相对作用：2.鉴定肿瘤微环境中产生特定趋化因子的细胞类型，并确定选定的趋化因子在T细胞募集中的作用；以及3.研究黑色素瘤肿瘤细胞中Notch信号在建立肿瘤微环境和介导T细胞介导的杀伤抵抗中的作用。这项工作的最终目标是开发策略，通过克服黑色素瘤肿瘤微环境中的限制，促进抗肿瘤免疫反应的效应阶段，从而确定具有未来临床应用潜力的方法。

DESCRIPTION (provided by applicant): Recent observations have indicated that features of the melanoma tumor microenvironment likely determine whether tumor regression versus resistance occurs in response to a successfully generated anti-tumor T cell response. Our preliminary gene expression profiling data on the melanoma tumor microenvironment from patients with advanced disease have suggested two categories of downstream defects: failure to recruit activated T cells into metastatic sites, and presence of immunosuppressive mechanisms in the microenvironment of tumors that have indeed recruited T cells. T cell trafficking has been associated with expression of specific chemokines within tumor sites. Identified immune resistance mechanisms include expression of the inhibitory ligand PD-L1 on the tumor cells themselves, the presence of FoxP3+ regulatory T cells, the tryptophan-catabolizing enzyme IDO expressed by dendritic-like cells and endothelial cells, and the anergy-promoting conditions of having poor B7 expression by APC populations. An additional observation has linked high levels of Notch signaling in melanoma tumors with resistance to immunotherapy and poor T cell recruitement, thus offering a potential link between tumor cell biology and establishment of features of the surrounding microenvironment. These observations have crystalized into the following Specific Aims: 1. To examine the relative contribution of PD-1, regulatory T cells, IDO, and anergy in limiting immune-mediated tumor regression in a mouse preclinical model: 2. To identify cell types producing specific chemokines in the tumor microenvironment and determine the role of selected chemokines in T cell recruitment; and 3. To investigate the role of Notch signaling in melanoma tumor cells in establishing the tumor microenvironment and mediating resistance to T cell-mediated killing. The ultimate goal of this work is to develop strategies to facilitate the effector phase of the anti-tumor immune response by overcoming limitations within the melanoma tumor microenvironment, thus identifying approaches with potential for future clinical application.