Melanoma Immunotherapy with GPR182 blockade

项目摘要 GPR182阻断对黑色素瘤的免疫治疗作用 免疫检查点抑制剂治疗极大地提高了晚期黑色素瘤患者的存活率。 然而，超过一半的患者并没有从这种疗法中受益。其中一个主要障碍是许多黑色素瘤 组织中缺乏CD8效应T细胞的浸润。趋化因子如CXCL9和CXCL10在 调节效应性T细胞向肿瘤的渗透。非典型趋化因子受体是一组gpr蛋白。 在非免疫细胞中表达，通过内吞作用主动调节趋化因子。我们的研究揭示了 GPR182 AS 一种新的Ackr受体在瘤周淋巴管中选择性上调。我们的初步结果 表明该分子在小鼠体内的基因缺失导致效应器T细胞浸润增加，从而导致 在几种小鼠黑色素瘤模型中抑制肿瘤生长。我们进一步发现GPR182与 趋化因子在体外的广泛应用和CXCR3的阻断完全取消了对小鼠抗肿瘤免疫的改善 GPR182缺陷小鼠。在这里，我们假设GPR182通过限制 趋化因子的可获得性和靶向这一途径提供了一种转化免疫寒冷的新方法 从黑色素瘤到辣妹。我们将剖析GPR182和趋化因子之间的分子相互作用，以及 检测GPR182对肿瘤细胞趋化因子的吞噬作用。GPR182抑制GPR182的机制 将研究抗肿瘤T细胞反应。最后，GPR182单抗的体内抗肿瘤作用 将对阻断GPR182和趋化因子之间相互作用的抗体进行评估。到完工时 在这些研究中，我们将确定一种新的免疫冷性黑色素瘤发炎策略，并将有一个 更好地了解淋巴管在黑色素瘤中的免疫调节作用。

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.