AAV-sBTLA facilitates HSP70 vaccine-triggered prophylactic antitumor immunity against a murine melanoma pulmonary metastasis model in vivo Article

International Collaboration

cited authors

  • Han, Lingfei, Wang, Wei, Lu, Jiahong, Kong, Fanfei, Ma, Ge, Zhu, Yiping, Zhao, Dong, Zhu, Jianlong, Shuai, Wen, Zhou, Qian, Chen, Ping, Ye, Lei, Tao, Jie, Ahmad, Sarfraz, Li, Fang, Sun, Jing

funding text

  • Supported in part by grants from the National Natural Science Foundation of China (81001153; 81072132; 81372781), Shanghai Rising-Star Program (11QA1405200), Science and Technology Commission of Shanghai Municipality (124119A3800; 124119A3801) and Health Bureau of Shanghai (2010Y150; 20114150; 20124111).

abstract

  • Activation of the BTLA-HVEM co-inhibitory signaling pathway impairs antitumor immunity. Our previous study demonstrated that the extracellular domain of murine BTLA (the soluble form of BTLA) can facilitate HSP70 vaccine-triggered antitumor immunity by blocking BTLA-HVEM interactions in a murine TC-1 non-metastatic tumor model. However, it is unknown whether this strategy has beneficial effects on highly malignant metastatic tumors, such as melanoma. To address this question, we expressed the soluble form of BTLA (sBTLA) in combination with HSP70 vaccine and examined the resulting antitumor activity in a melanoma pulmonary metastasis model. A recombinant adeno-associated virus (AAV) vector was used for the sBTLA gene delivery because of its high transfection efficiency and low toxicity. In vitro expression of AAV-sBTLA enhanced lymphocyte activation and induced specific cytotoxicity against B16F1 murine melanoma cells, while in vivo administration of AAV-sBTLA plus HSP70 vaccine by tail vein injection exerted a limited, late-stage antitumor effect against the existing B16F1 cells. However, the combination treatment generated a potent prophylactic antitumor response in the melanoma lung metastasis model in B6 mice. In this case, most of the metastatic foci were inhibited, and mouse survival was prolonged. Furthermore, the Th1 cytokines IL-2 and IFN-gamma were up-regulated, while the negative regulatory molecules IL-10 and TGF-beta were down-regulated. The number of regulatory T cells also decreased in the tumor environment. Therefore, AAV-sETLA plus HSP70 vaccine may have therapeutic potential for the prevention of metastatic melanoma. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

authors

Publication Date

  • November 28, 2014

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published in

category

start page

  • 398

end page

  • 406

volume

  • 354

issue

  • 2

WoS Citations

  • 6

WoS References

  • 37