Tumor-associated blood vessels and lymphatics are abnormal and dysfunctional. These are hallmarks of the tumor microenvironment, which has an immunosuppressive nature, such as through hypoxia. Treatment with anti-death receptor5 (DR5) monoclonal antibody MD5-1, which induces tumor cell death, is a potent anti-tumor immunotherapy. Generally, MD5-1 induces cell death mainly via antigen presenting cells (APCs) and generates tumor-specific effector T cells. To date, the effects of a simultaneous functional improvement of abnormal blood vessels and lymphatics on the immune microenvironment are largely unknown. A combination therapy using sunitinib, vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor inhibitor, and MD5-1 substantially inhibited tumor growth. Sunitinib improved pericyte coverage on endothelial cells and the expression levels of regulator of G-protein signaling 5, suggesting blood vessel normalization. Sunitinib also increased lymph flow from tumors to central lymph nodes, suggesting improved lymphatic function. In concordance with improved vasculature functions, sunitinib alleviated the tumor hypoxia, suggesting an improved tumor microenvironment. Indeed, the combination therapy induced strong activation of CD8+ T cells and dendritic cells in draining lymph nodes. The combination therapy reduced the ratio of immune-suppressive T regulatory cells in the tumors and draining lymph nodes. The combination therapy enhanced the numbers and activation of tumor-infiltrating CD8+ T cells. CD4 and/or CD8 depletion, or APC inhibiting experiments showed the contribution of CD8+ T cells and APCs to the combination therapy. These findings suggest that targeting blood vessels and lymphatics may have potential benefits for immunotherapy mediated by CD8+ T cells and APCs.

中文翻译：

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舒尼替尼对靶向死亡受体的肿瘤微环境和免疫疗法的有益作用5。

肿瘤相关血管和淋巴管异常且功能失调。这些是肿瘤微环境的标志，其具有免疫抑制性质，例如通过缺氧。抗死亡受体5（DR5）单克隆抗体MD5-1的治疗可诱导肿瘤细胞死亡，是一种有效的抗肿瘤免疫疗法。通常，MD5-1主要通过抗原呈递细胞（APC）诱导细胞死亡，并产生肿瘤特异性效应T细胞。迄今为止，异常血管和淋巴管同时功能改善对免疫微环境的影响尚不清楚。使用舒尼替尼，血管内皮生长因子（VEGF）和血小板衍生的生长因子受体抑制剂以及MD5-1的联合疗法可显着抑制肿瘤生长。舒尼替尼改善了内皮细胞的周细胞覆盖率和G蛋白信号调节剂5的表达水平，表明血管正常化。舒尼替尼还增加了从肿瘤到中央淋巴结的淋巴流量，表明淋巴功能得到改善。与改善的脉管系统功能一致，舒尼替尼减轻了肿瘤的缺氧，提示肿瘤微环境得到改善。实际上，联合疗法在引流淋巴结中诱导了CD8 + T细胞和树突状细胞的强烈活化。联合疗法降低了肿瘤和引流淋巴结中免疫抑制性T调节细胞的比例。联合疗法增强了肿瘤浸润性CD8 + T细胞的数量和激活。CD4和/或CD8耗尽，或APC抑制实验显示CD8 + T细胞和APC对联合治疗的贡献。这些发现表明，靶向血管和淋巴管可能对CD8 + T细胞和APC介导的免疫治疗具有潜在的好处。