Berraondo Pedro, Nouzé Clémence, Préville Xavier, Ladant Daniel, Leclerc Claude
Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris, France.
Cancer Res. 2007 Sep 15;67(18):8847-55. doi: 10.1158/0008-5472.CAN-07-0321.
Targeting the human papillomavirus (HPV) E7 antigen to dendritic cells with the adenylate cyclase (CyaA) of Bordetella pertussis as a vaccine vector led to potent therapeutic immune responses against TC-1 tumors in a murine model of cervical carcinoma induced by HPV. However, as the time between tumor graft and vaccination increased, the antitumor efficacy of the CyaA-E7 vaccine gradually decreased. The vaccine had no effect if the tumor diameter was >8 mm. Analyses of regulatory cells recruited during TC-1 tumor growth revealed a high number of splenic MDSCs and a large percentage of regulatory T cells, particularly in the tumor. Administration of a tritherapy including CpG complexed with a cationic lipid, low-dose cyclophosphamide, and the CyaA-E7 vaccine completely overcame tumor-associated immunosuppression and eradicated large, established tumors in almost all treated animals. This strong antitumor response was followed by a large expansion of regulatory T cells in tumor, spleen, and tumor-draining lymph nodes and of splenic neutrophils. These findings indicate that immunotherapeutic strategies that simultaneously target innate, adaptive, and regulatory components of the immune system are effective in the eradication of large tumors.
以百日咳博德特氏菌的腺苷酸环化酶（CyaA）作为疫苗载体，将人乳头瘤病毒（HPV）E7抗原靶向树突状细胞，在由HPV诱导的宫颈癌小鼠模型中引发了针对TC-1肿瘤的强效治疗性免疫反应。然而，随着肿瘤移植与接种疫苗之间的时间增加，CyaA-E7疫苗的抗肿瘤功效逐渐降低。如果肿瘤直径>8毫米，该疫苗则无效。对TC-1肿瘤生长过程中募集的调节性细胞的分析显示，脾脏中存在大量髓源性抑制细胞（MDSC）以及很大比例的调节性T细胞，尤其是在肿瘤中。给予一种三联疗法，包括与阳离子脂质复合的CpG、低剂量环磷酰胺以及CyaA-E7疫苗，可完全克服肿瘤相关的免疫抑制，并在几乎所有接受治疗的动物中根除已形成的大肿瘤。这种强烈的抗肿瘤反应之后，肿瘤、脾脏和肿瘤引流淋巴结中的调节性T细胞以及脾脏中的中性粒细胞大量扩增。这些发现表明，同时靶向免疫系统的固有、适应性和调节成分的免疫治疗策略在根除大肿瘤方面是有效的。
