PD-L1和血管内皮生长因子双重阻断增强血行转移模型中脑转移的抗肿瘤效果

IF 4.2 3区 医学 Q2 ONCOLOGY
Chinami Masuda, Shinichi Onishi, Keigo Yorozu, Mitsue Kurasawa, Mamiko Morinaga, Daiko Wakita, Masamichi Sugimoto
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引用次数: 0

摘要

免疫疗法能改善癌症患者的生存预后,但在治疗脑转移瘤方面仍有未满足的临床需求。在此,我们利用小鼠模型研究了程序性死亡配体1(PD-L1)和血管内皮生长因子(VEGF)双重阻断对转移性脑肿瘤的抗肿瘤作用,并评估了治疗过程中的免疫反应。通过C3H/HeNCrl小鼠的颈内动脉移植稳定表达secNLuc报告基因的小鼠膀胱癌MBT2细胞,建立血源性脑转移后,我们观察到转移瘤不仅在脑实质中形成,而且在脑室中也形成。观察到的病理区域显示,脑室转移灶的组织学大小大于脑实质转移灶。就 Nluc 活性显示的全脑总肿瘤负荷而言,抗 PD-L1 抗体和抗血管内皮生长因子抗体的联合抗肿瘤效果强于单药。单用抗PD-L1抗体可增强区域淋巴结中CD8+T细胞的引诱作用,提高全脑中活化CD8+T细胞的比例,并增加脑实质中CD8+细胞的密度。此外,单用抗血管内皮生长因子抗体可降低脑室转移灶的微血管密度(MVD),而联合治疗可增加脑实质和脑室转移灶的瘤内CD8+细胞密度。这些结果表明,PD-L1 阻断不仅能增强脑转移灶病灶的癌症免疫力,还能增强转移灶区域淋巴结的癌症免疫力,而加入血管内皮生长因子阻断则能通过增加活化的 CD8+ T 细胞浸润和降低 MVD 增加抗肿瘤效果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

PD-L1 and VEGF dual blockade enhances anti-tumor effect on brain metastasis in hematogenous metastasis model.

PD-L1 and VEGF dual blockade enhances anti-tumor effect on brain metastasis in hematogenous metastasis model.

Immunotherapy improves survival outcomes in cancer patients, but there is still an unmet clinical need in the treatment of brain metastases. Here, we used a mouse model to investigate the antitumor effect of programmed death-ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) dual blockade on metastatic brain tumors and evaluated immune responses during treatment. After establishing hematogenous brain metastasis by transplanting murine bladder carcinoma MBT2 cells stably expressing secNLuc reporter via the internal carotid artery of C3H/HeNCrl mice, we observed the formation of metastases not only in the brain parenchyma but also in the ventricles. The observed pathological areas showed that metastases in the ventricle were histologically larger than that in the brain parenchyma. Regarding the total tumor burden in the whole brain as revealed by Nluc activities, the combination of anti-PD-L1 antibody and anti-VEGF antibody showed a stronger anti-tumor effect than each single agent. Anti-PD-L1 antibody alone enhanced CD8+ T cell priming in regional lymph nodes, increased the proportion of activated CD8+ T cells in whole brain, and increased the density of CD8+ cells in the brain parenchyma. Furthermore, anti-VEGF antibody alone decreased microvessel density (MVD) in ventricular metastases, and the combination treatment increased intratumoral CD8+ cell density in the brain parenchyma and ventricular metastases. These results suggest that PD-L1 blockade enhanced cancer immunity not only in brain metastases lesions but also in the regional lymph nodes of the metastases, and that the addition of VEGF blockade increased the antitumor effect by increasing the infiltration of activated CD8+ T cell and decreasing MVD.

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来源期刊
CiteScore
7.80
自引率
5.00%
发文量
55
审稿时长
12 months
期刊介绍: The Journal''s scope encompasses all aspects of metastasis research, whether laboratory-based, experimental or clinical and therapeutic. It covers such areas as molecular biology, pharmacology, tumor biology, and clinical cancer treatment (with all its subdivisions of surgery, chemotherapy and radio-therapy as well as pathology and epidemiology) insofar as these disciplines are concerned with the Journal''s core subject of metastasis formation, prevention and treatment.
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