期刊
CELLULAR IMMUNOLOGY
卷 310, 期 -, 页码 89-98出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.cellimm.2016.08.006
关键词
Fibroblast activation protein alpha; Prime-boost strategy; Cyclophosphamide; Immunosuppression; Cancer vaccine
资金
- Specialized Research Fund for the National Natural Science Foundation of China [31300765, 81301803]
- Specialized Research Fund for the Doctoral Program of Higher Education (New Teachers) [20120061120025]
- Jilin Province Science and Technology Development Program [20130522006JH, 20160519018JH]
- National Science and Technology Major Project of the Ministry of Science and Technology of China [2014ZX09304314-001-002, 2012ZX10001009-2]
- Jilin Province Science and Technology Development Plan [20140309007YY]
- Norman Bethune Program of Jilin University [2015305]
Fibroblast activation protein alpha (FAP alpha) is expressed in cancer-associated fibroblasts (CAFs), which are the main type of cells in the tumor microenvironment. CAFs exert immunosuppressive activity, which can weaken the effects of cancer immunotherapy and mainly account for poor outcomes with therapeutic vaccines. To better target and destroy CAFs, a FAP alpha vaccine using a modified vaccinia ankara (MVA) vector was constructed and used with a DNA vaccine reported in our previous work for heterologous prime-boost immunizations in mice. This strategy to generate anti-tumor immunity partly reduced 4T1 tumor growth through producing FAP alpha-specific cytotoxic T lymphocyte responses in a preventive model, but the effect required improvement. Combining the FAP alpha-based cancer vaccines (CpVR-FAP/MVA-FAP) with cyclophosphamide (CY), which can be used not only as a chemotherapeutic but also an immunomodulatory agent to promote a shift from immunosuppression to immunopotentiation, resulted in markedly enhanced tumor growth inhibition compared with the CpVR-FAP/MVA-FAP group. This strategy achieved synergistic effects in a therapeutic model by improving the tumor inhibition rate by 2.5-fold (90.2%), significantly enhancing cellular immunity and prolonging the survival of 4T1 tumor-bearing mice by 35% compared with the PBS group. Furthermore, CAFs, stromal factors and immunosuppressive factors such as IL-10 and Tregs were also markedly decreased by the CY combination. These results indicated that FAP alpha-targeted MVA boosting in combination with CY is an effective approach to improving specific anti-tumor immune responses through overcoming immunosuppression. This study may offer important advances in research on clinical cancer immunotherapies by modulating immunosuppressive factors. (C) 2016 Elsevier Inc. All rights reserved.
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