A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism
A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism
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DOI：
10.1158/1078-0432.ccr-07-0374
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发表时间：
2007-07-01
影响因子：
11.5
通讯作者：
Emens, Leisha A.
中科院分区：
文献类型：
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作者：
Manning, Elizabeth A.;Ullman, John G. M.;Emens, Leisha A.
鉴于复杂的肿瘤微环境，靶向多种细胞成分可能是最有效的癌症治疗策略。因此，我们测试是否抗血管生成和免疫为基础的治疗可能协同作用的活性特征的DC 101，抗血管生成的单克隆抗体特异性血管内皮生长因子受体-2（VEGF-R2），单独和HER-2/neu（neu）-靶向vaccination.Experimental Design：Neu-expressing乳腺肿瘤进行了测量治疗非耐受FVB小鼠和免疫耐受neu转基因（neu-N）小鼠。结果：DC 101能抑制肿瘤血管生成，促进肿瘤细胞凋亡，并能抑制肿瘤细胞的增殖和凋亡。尽管DC 101增加了免疫抑制细胞因子VEGF的血清水平，但没有检测到全身免疫抑制的证据。此外，DC 101并不阻碍肿瘤浸润淋巴细胞的流入。在FVB小鼠中，DC 101部分通过T细胞依赖性机制抑制肿瘤生长，导致肿瘤特异性CD 8（+）T细胞增加和肿瘤消退。将DC 101与neu特异性疫苗接种相结合加速了肿瘤消退，增强了CD 8+细胞毒性T细胞的溶解活性。在耐受性neu-N小鼠中，DC 101仅延迟肿瘤生长，而不诱导明显的肿瘤消退或抗原特异性T细胞活化。值得注意的是，减轻免疫耐受，通过抑制调节性T细胞的活性与环磷酰胺揭示DC 101介导的增强抗肿瘤反应接种neu-N mice.Conclusions：这是第一次报告的DC 101诱导的抗肿瘤免疫反应。它建立了肿瘤特异性T细胞应答的诱导作为用DC 101靶向VEGF-R2的结果之一。这些数据支持多靶点癌症治疗的发展，结合免疫和抗血管生成剂的临床翻译。
Purpose: Given the complex tumor microenvironment, targeting multiple cellular components may be the most effective cancer treatment strategy. Therefore, we tested whether antiangiogenic and immune-based therapy might synergize by characterizing the activity of DC101, an antiangiogenic monoclonal antibody specific for vascular endothelial growth factor receptor-2 (VEGF-R2), alone and with HER-2/neu (neu)-targeted vaccination.Experimental Design: Neu-expressing breast tumors were measured in treated nontolerant FVB mice and immune-tolerant neu transgenic (neu-N) mice. Neu-specific and tumor cell specific immune responses were assessed by intracellular cytokine staining, ELISPOT and CTL assays.Results: DC101 decreased angiogenesis and increased tumor cell apoptosis. Although DC101 increased serum levels of the immunosuppressive cytokine VEGF, no evidence of systemic immune inhibition was detected. Moreover, DC101 did not impede the influx of tumor-infiltrating lymphocytes. In FVB mice, DC101 inhibited tumor growth in part through a T cell-dependent mechanism, resulting in both increased tumor-specific CD8(+) T cells and tumor regression. Combining DC101 with neu-specific vaccination accelerated tumor regression, augmenting the lytic activity of CD8+ cytotoxic T cells. In tolerant neu-N mice, DC101 only delayed tumor growth without inducing frank tumor regression or antigen-specific T-cell activation. Notably, mitigating immune tolerance by inhibiting regulatory T cell activity with cyclophosphamide revealed DC101-mediated augmentation of antitumor responses in vaccinated neu-N mice.Conclusions: This is the first report of DC101-induced antitumor immune responses. It establishes the induction of tumor-specific T-cell responses as one consequence of VEGF-R2 targeting with DC101. These data support the development of multitargeted cancer therapy combining immune-based and antiangiogenic agents for clinical translation.