Induction of systemic immune responses and reversion of immunosuppression in the tumor microenvironment by a therapeutic vaccine for cervical cancer
Induction of systemic immune responses and reversion of immunosuppression in the tumor microenvironment by a therapeutic vaccine for cervical cancer
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DOI：
10.1007/s00262-020-02651-3
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发表时间：
2020-07-01
影响因子：
5.8
通讯作者：
Wang, Xuelian
中科院分区：
文献类型：
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作者：
Che, Yuxin;Yang, Yang;Wang, Xuelian
宫颈癌是世界范围内女性生殖道最常见的恶性肿瘤。持续性人乳头瘤病毒（HPV）感染与宫颈癌的发生密切相关。目前没有获得许可的宫颈癌治疗性HPV疫苗。在我们以前的研究中，我们证明了含有HPV 16 E7 43 - 77肽和佐剂非甲基化胞嘧啶-磷酸-鸟苷寡核苷酸的疫苗对宫颈癌有显著的预防和治疗作用。在目前的研究中，我们全面评估了疫苗对宫颈癌小鼠模型全身免疫应答和肿瘤微环境（TME）的影响。结果显示，疫苗的施用诱导了脾IFN-γ产生性CD4和CD8 T细胞以及肿瘤浸润性CD4和CD8 T细胞的显著增加。此外，在疫苗组中观察到脾MDSC和TcM以及瘤内MDSC、TcM和2型极化肿瘤相关巨噬细胞的显著减少。TME中细胞因子、趋化因子和基质金属蛋白酶（MMP）的谱显示，在疫苗组中，IL-2、IL-12、TNF-α、IFN-γ、CCL-20、CXCL-9、CXCL-10和CXCL-14的表达显著增加，而IL-6、IL-10、TGF-β、CCL-2、CCL-3、CCL-5、CXCL-8、MMP-2、MMP-9和VEGF的表达降低。细胞增殖指标Ki67、凋亡调节蛋白p53和血管生成标志物CD31的表达在疫苗组中显著降低。总之，疫苗逆转了致耐受性全身和局部TME免疫抑制，并诱导了稳健的抗肿瘤免疫应答，从而抑制了已建立的植入肿瘤。
Cervical cancer is the most common malignant tumor of the genital tract in females worldwide. Persistent human papillomavirus (HPV) infection is closely associated with the occurrence of cervical cancer. No licensed therapeutic HPV vaccines for cervical cancer are currently available. In our previous study, we demonstrated that the vaccine containing the HPV16 E7 43-77 peptide and the adjuvant unmethylated cytosine-phosphate-guanosine oligodeoxynucleotide elicited significant prophylactic and therapeutic effects on cervical cancer. In the current study, we comprehensively evaluated the effect of the vaccine on systemic immune responses and the tumor microenvironment (TME) in a mouse model of cervical cancer. The results showed that the administration of the vaccine induced a significant increase in splenic IFN-gamma-producing CD4 and CD8 T cells as well as tumor infiltrating CD4 and CD8 T cells. Moreover, marked decreases in splenic MDSCs and Tregs as well as intratumoral MDSCs, Tregs and type 2-polarized tumor-associated macrophages were observed in the vaccine group. The profile of cytokines, chemokines and matrix metalloproteinases (MMPs) in the TME revealed significantly increased expression of IL-2, IL-12, TNF-alpha, IFN-gamma, CCL-20, CXCL-9, CXCL-10 and CXCL-14 and decreased expression of IL-6, IL-10, TGF-beta, CCL-2, CCL-3, CCL-5, CXCL-8, MMP-2, MMP-9 and VEGF in the vaccine group. The expression of the cell proliferation indicator Ki67, apoptosis regulatory protein p53 and angiogenesis marker CD31 was significantly decreased in the vaccine group. In conclusion, the vaccine reversed tolerogenic systemic and local TME immunosuppression and induced robust antitumor immune responses, which resulted in the inhibition of established implanted tumors.