期刊
ONCOTARGET
卷 6, 期 32, 页码 32426-32438出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5856
关键词
CD8(+)T cells; vaccination; mesothelioma; antigen spreading; MDSCs
资金
- Hong Kong Pneumoconiosis Compensation Fund Board (PCFB) [RGC/GRF762712, RGC/HKU5/CRF/13G]
- HKU-UDF
- HKU-LKSFM matching fund
- Hong Kong Scholars Program [HJ2012056]
- Chinese Postdoctoral Science Foundation [2013M542441, 2014T70981]
A key focus in cancer immunotherapy is to investigate the mechanism of efficacious vaccine responses. Using HIV-1 GAG-p24 in a model PD1-based DNA vaccine, we recently reported that vaccine-elicited CD8(+)T cells conferred complete prevention and therapeutic cure of AB1-GAG malignant mesothelioma in immunocompetent BALB/c mice. Here, we further investigated the efficacy and correlation of protection on the model vaccine-mediated antigen spreading against wild-type AB1 (WT-AB1) mesothelioma. We found that this vaccine was able to protect mice completely from three consecutive lethal challenges of AB1-GAG mesothelioma. Through antigen spreading these animals also developed tumor-specific cytotoxic CD8(+)T cells, but neither CD4(+)T cells nor antibodies, rejecting WT-AB1 mesothelioma. A majority of these protected mice (90%) were also completely protected against the lethal WT-AB1 challenge. Adoptive cell transfer experiments further demonstrated that antigen spreading-induced CD8(+)T cells conferred efficacious therapeutic effects against established WT-AB1 mesothelioma and prevented the increase of exhausted PD-1(+)and Tim-3 (+)CD8(+)T cells. A significant inverse correlation was found between the frequency of functional PD1-Tim3-CD8(+)T cells and that of MDSCs or tumor mass in vivo. Mechanistically, we found that WT-AB1 mesothelioma induced predominantly polymorphonuclear (PMN) MDSCs in vivo. In co-cultures with efficacious CD8(+)T cells, a significant number of PMN-MDSCs underwent apoptosis in a dose-dependent way. Our findings indicate that efficacious CD8(+)T cells capable of eliminating both tumor cells and MDSCs are likely necessary for fighting wild-type malignant mesothelioma.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据