Fricke Ingo, Mirza Noweeda, Dupont Jakob, Lockhart Craig, Jackson Autumn, Lee Ji-Hyun, Sosman Jeffrey A, Gabrilovich Dmitry I
H. Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida 33612, USA.
Clin Cancer Res. 2007 Aug 15;13(16):4840-8. doi: 10.1158/1078-0432.CCR-07-0409.
Induction of antitumor immune responses requires adequate function of dendritic cells. Dendritic cell defects in cancer patients have been implicated in tumor escape and the limited efficacy of cancer vaccines. Previous studies have shown that vascular endothelial growth factor (VEGF) plays a major role in abnormal dendritic cell differentiation and function in cancer. It has been proposed that inhibition of VEGF may result in improved immune responses. The goal of this study was to test this hypothesis.
Fifteen patients with refractory solid tumors were enrolled into a phase I clinical trial of VEGF-Trap. Phenotype and function of different subsets of mononuclear cells were measured before and at different time points after the start of treatment.
VEGF-Trap treatment did not affect the total population of dendritic cells, their myeloid or plasmacytoid subsets, myeloid-derived suppressor cells (MDSC), or regulatory T cells. It significantly increased the proportion of mature dendritic cells. However, that improvement was not associated with an overall increase in immune responses to various antigens and mitogens. A subset analysis revealed significant improvement in immune responses in patients who had no increase in the proportion of MDSC. An improvement in immune responses was absent in patients with an increase in the proportion of MDSC.
Inhibition of VEGF signaling may improve differentiation of dendritic cells in cancer patients. However, it was not sufficient to improve immune responses. This shows multifaceted nature of immune deficiency and points out to the need for complex approach to modulation of immune reactivity in cancer.
诱导抗肿瘤免疫反应需要树突状细胞具备充分的功能。癌症患者的树突状细胞缺陷与肿瘤逃逸及癌症疫苗疗效有限有关。先前的研究表明，血管内皮生长因子（VEGF）在癌症中异常的树突状细胞分化和功能中起主要作用。有人提出抑制VEGF可能会改善免疫反应。本研究的目的是验证这一假设。
15例难治性实体瘤患者参加了VEGF-Trap的I期临床试验。在治疗开始前及不同时间点测量单核细胞不同亚群的表型和功能。
VEGF-Trap治疗不影响树突状细胞的总数、其髓样或浆细胞样亚群、髓样来源的抑制细胞（MDSC）或调节性T细胞。它显著增加了成熟树突状细胞的比例。然而，这种改善与对各种抗原和有丝分裂原的免疫反应总体增加无关。亚组分析显示，MDSC比例未增加的患者免疫反应有显著改善。MDSC比例增加的患者免疫反应未改善。
抑制VEGF信号传导可能会改善癌症患者树突状细胞的分化。然而，这不足以改善免疫反应。这显示了免疫缺陷的多面性，并指出在癌症中调节免疫反应性需要采用综合方法。
