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在成功产生抗肿瘤T细胞反应后，肿瘤是否会发生消退或耐药性。我们对晚期黑色素瘤患者肿瘤微环境的初步基因表达谱数据表明了两类下游缺陷：无法将活化的T细胞募集到转移部位，以及肿瘤微环境中确实存在募集T细胞的免疫抑制机制。T细胞运输与肿瘤部位特定趋化因子的表达有关。已确定的免疫抵抗机制包括肿瘤细胞本身的抑制性配体PD-L1的表达，FoxP3+调节性T细胞的存在，树突样细胞和内皮细胞表达的色氨酸分解代谢酶IDO，以及APC群体B7表达差的促能条件。另一项观察发现，黑素瘤中Notch信号的高水平与免疫治疗抵抗和T细胞募集不足有关，从而提供了肿瘤细胞生物学与周围微环境特征建立之间的潜在联系。这些观察总结为以下具体目标：在小鼠临床前模型中，研究PD-1、调节性T细胞、IDO和能量在限制免疫介导的肿瘤消退中的相对贡献。鉴定肿瘤微环境中产生特定趋化因子的细胞类型，并确定所选趋化因子在T细胞募集中的作用；和3。探讨Notch信号在黑色素瘤细胞中建立肿瘤微环境和介导T细胞介导杀伤的作用。这项工作的最终目标是通过克服黑色素瘤肿瘤微环境中的限制，制定促进抗肿瘤免疫反应效应期的策略，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.