Melanoma Immunotherapy with GPR182 blockade

项目摘要 使用GPR182阻断的黑色素瘤免疫疗法 免疫检查点抑制剂治疗大大提高了晚期黑色素瘤患者的生存率。 然而，超过一半的患者没有从这种治疗中受益。其中一个主要障碍是许多黑色素瘤 组织缺乏效应CD8+ T细胞浸润。趋化因子如CXCL9和CXCL10在免疫调节中起重要作用。 调节效应T细胞向肿瘤中的浸润。非典型趋化因子受体是一组GPCR蛋白 在非免疫细胞中表达，通过内吞作用积极调节趋化因子。我们的研究发现 GPR182 作为 一种新的在瘤周肿瘤中选择性上调的ACKR受体。我们的初步结果 表明小鼠中该分子的遗传缺失导致效应T细胞浸润增加，从而导致免疫缺陷。 在几种小鼠黑色素瘤模型中肿瘤生长的延迟。我们进一步发现GPR182与 CXCR3的阻断完全消除了体外培养中提高的抗肿瘤免疫力。 GPR182缺陷小鼠。在这里，我们假设GPR182通过限制抗肿瘤免疫反应来抑制抗肿瘤免疫反应 趋化因子的可用性和靶向这一途径提供了一种新的方法， 从黑色素瘤到性感的我们将剖析GPR182和趋化因子之间的分子相互作用， 用GPR182检测肿瘤细胞对趋化因子的内吞作用。GPR182抑制的机制 将研究抗肿瘤T细胞反应。最后，研究了GPR182单克隆抗体的体内抗肿瘤作用。 将评估阻断GPR182和趋化因子之间相互作用的抗体。通过完成 在这些研究中，我们将确定一种新的免疫性冷黑色素瘤炎症策略， 更好地理解免疫调节剂在黑色素瘤中的作用。

Project Summary Melanoma immunotherapy with GPR182 blockade Immune checkpoint inhibitor therapy has greatly improved survival of patients with late-stage melanoma. However, over half of patients do not benefit from this therapy. One of the main hurdles is that many melanoma tissues lack effector CD8+ T cell infiltrates. Chemokines such as CXCL9 and CXCL10 play an important role in regulating effector T cell infiltration into the tumors. Atypical Chemokine Receptors are a group of GPCR proteins that are expressed in non-immune cells to actively regulate chemokines by endocytosis. Our studies uncovered GPR182 as a novel ACKR receptor selectively upregulated in peritumoral lymphatics. Our preliminary results indicated that genetic deletion of this molecule in mice led to increased effector T cell infiltration and thereby the retardment of tumor growth in several mouse melanoma models. We further found that GPR182 interacts with chemokines broadly in vitro and blockade of CXCR3 completely abolished improved antitumor immunity in GPR182- deficient mice. Here we hypothesize that GPR182 inhibits anti-tumor immune response by limiting chemokine availability and targeting this pathway offers a novel approach to converting immunologically cold melanoma to hot ones. We will dissect the molecular interaction between GPR182 and chemokines, and also examine the chemokine endocytosis by GPR182 with tumors. The mechanisms by which GPR182 inhibits antitumor T cell response will be investigated. Finally, the in vivo antitumor effect of a GPR182 monoclonal antibody, which blocks the interaction between GPR182 and chemokines, will be assessed. By the completion of these studies, we will identify a new strategy of inflaming immunologically cold melanoma and will have a better understanding of the immunomodulatory role of the lymphatics in melanoma.