The CD93 pathway and melanoma therapy

项目摘要/摘要 免疫检查点阻滞剂治疗最近极大地提高了晚期糖尿病患者的存活率 黑色素瘤。然而，约三分之二的患者并未从这种疗法中受益。其中一个主要障碍是太多 黑色素瘤组织缺乏CD8+T细胞。未成熟和功能障碍的血管主动限制T 细胞渗入。最近，血管正常化已被证明能够促进效应者免疫。 细胞浸润，提高癌症免疫治疗水平。一条新的路径 IGFBP7/CD93相互作用，两者在肿瘤血管中选择性上调。我们的预赛 研究表明，在体内破坏这种相互作用可以使肿瘤血管正常化，从而减少缺氧和改善 小鼠黑色素瘤模型中的肿瘤灌注。我们对肿瘤组织的检查显示，阻断这一点 途径可激活肿瘤血管，促进T细胞浸润，限制髓系来源 肿瘤中的抑制细胞。这里我们假设这一途径的上调与肿瘤的发生有关 血管异常和靶向该通路将为促进黑色素瘤提供新的途径 免疫疗法。我们将剖析这一途径是如何在肿瘤中被诱导并最终导致肿瘤的。 血管功能障碍，然后是肿瘤生长。CD93调节免疫细胞的机制 将评估渗透以及其表达导致对抗PD1治疗的抵抗。由 完成这些研究，我们将深入了解这一途径在癌症中的生物学作用 黑色素瘤的微环境，更重要的是，提供了一种促进免疫治疗的新策略 黑色素瘤。 我们的 研究 未覆盖

PROJECT SUMMARY/ABSTRACT Immune checkpoint blocker therapy has recently greatly improved survival of patients with late- stage melanoma. However, about 2/3 of patients do not benefit from this therapy. One of main hurdles is that many melanoma tissues lack effector CD8+ T cells. The immature and dysfunctional blood vessels actively limit T cell infiltration. Recently vascular normalization has been demonstrated to be able to facilitate effector immune cell infiltration and to improve cancer immunotherapy. a novel pathway in the IGFBP7/CD93 interaction, both of which are selectively upregulated in tumor vasculature. Our preliminary study indicates that disrupting this interaction in vivo normalizes tumor vessels to reduce hypoxia and improve tumor perfusion in mouse melanoma models. Our examination of tumor tissues reveals that blockade of this pathway could reinvigorate tumor blood vessels to promote T cell infiltration while limit myeloid-derived suppressor cells in the tumor. Here we hypothesize that upregulation of this pathway contributes to the tumor vascular abnormality and targeting this pathway will offer a novel approach to facilitate melanoma immunotherapy. We will dissect how this pathway is induced in the tumor and consequently leads to tumor vascular dysfunction and then tumor outgrowth. The mechanisms by which CD93 regulates immune cell infiltration, as well as its expression causing resistance to anti-PD1 therapy, will be evaluated. By the completion of these studies, we will gain insight into the biological role of this pathway in the cancer microenvironment of melanoma and, more importantly, provide a new strategy of promoting immunotherapy in melanoma. Our studies uncovered