Department of Biochemistry, The Masonic Cancer Center, University of Minnesota, Minnesota 55455, USA.
Clin Cancer Res. 2011 May 15;17(10):3134-45. doi: 10.1158/1078-0432.CCR-10-2443. Epub 2011 Jan 20.
Tumor-released proangiogenic factors suppress endothelial adhesion molecule (EAM) expression and prevent leukocyte extravasation into the tumor. This is one reason why immunotherapy has met with limited success in the clinic. We hypothesized that overcoming EAM suppression with angiogenesis inhibitors would increase leukocyte extravasation and subsequently enhance the effectiveness of cellular immunotherapy.
Intravital microscopy, multiple color flow cytometry, immunohistochemistry, and various tumor mouse (normal and T-cell deficient) models were used to investigate the temporal dynamics of cellular and molecular events that occur in the tumor microenvironment during tumor progression and angiostatic intervention.
We report that while EAM levels and T-cell infiltration are highly attenuated early on in tumor growth, angiostatic therapy modulates these effects. In tumor models with normal and T-cell-deficient mice, we show the active involvement of the adaptive immune system in cancer and differentiate antiangiogenic effects from antiangiogenic mediated enhancement of immunoextravasation. Our results indicate that a compromised immune response in tumors can be obviated by the use of antiangiogenic agents. Finally, with adoptive transfer studies in mice, we show that a phased combination of angiostatic therapy and T-cell transfer significantly (P < 0.0013) improves tumor growth inhibition.
This research contributes to understand the cellular mechanism of action of angiostatic agents and the immune response within the tumor microenvironment, in particular as a consequence of the temporal dynamics of EAM levels. Moreover, our results suggest that adjuvant therapy with angiogenesis inhibitors holds promise for cellular immunotherapy in the clinic.
肿瘤释放的促血管生成因子抑制内皮细胞黏附分子（EAM）的表达，阻止白细胞渗出到肿瘤中。这也是免疫疗法在临床上收效甚微的原因之一。我们假设，用血管生成抑制剂克服 EAM 抑制作用会增加白细胞渗出，进而增强细胞免疫疗法的效果。
利用活体显微镜、多色流式细胞术、免疫组织化学和各种肿瘤小鼠（正常和 T 细胞缺陷）模型，研究肿瘤进展和血管抑制干预过程中肿瘤微环境中细胞和分子事件的时间动态变化。
我们报告称，虽然 EAM 水平和 T 细胞浸润在肿瘤生长早期就高度减弱，但血管抑制治疗会调节这些效应。在正常和 T 细胞缺陷小鼠的肿瘤模型中，我们显示了适应性免疫系统在癌症中的积极参与，并区分了抗血管生成作用和抗血管生成介导的免疫细胞外渗增强作用。我们的结果表明，使用抗血管生成药物可以避免肿瘤中受损的免疫反应。最后，通过在小鼠中的过继转移研究，我们表明血管抑制治疗和 T 细胞转移的分阶段联合显著（P < 0.0013）抑制了肿瘤生长。
这项研究有助于理解血管生成抑制剂的细胞作用机制以及肿瘤微环境中的免疫反应，特别是 EAM 水平的时间动态变化的影响。此外，我们的结果表明，抗血管生成抑制剂的辅助治疗有望在临床上用于细胞免疫疗法。
