237 296

Cited 0 times in

Prime-boost immunization by both DNA vaccine and oncolytic adenovirus expressing GM-CSF and shRNA of TGF-β2 induces anti-tumor immune activation

Authors
 So Young Kim  ;  Dongxu Kang  ;  Hye Jin Choi  ;  Yeonsoo Joo  ;  Joo-Hang Kim  ;  Jae J. Song 
Citation
 ONCOTARGET , Vol.8(9) : 15858-15877, 2017 
Journal Title
ONCOTARGET
Issue Date
2017
MeSH
Adenoviridae/genetics* ; Adenoviridae/metabolism* ; Animals ; Cell Line, Tumor ; Disease Models, Animal ; Granulocyte-Macrophage Colony-Stimulating Factor/genetics* ; Humans ; Mice ; Mice, Inbred C57BL ; Transfection ; Transforming Growth Factor beta2/genetics* ; Vaccines, DNA/genetics*
Keywords
DNA vaccine ; GM-CSF ; MART1 ; TGF-β2 ; oncolytic adenovirus
Abstract
A successful DNA vaccine for the treatment of tumors should break established immune tolerance to tumor antigen. However, due to the relatively low immunogenicity of DNA vaccines, compared to other kinds of vaccines using live virus or protein, a recombinant viral vector was used to enhance humoral and cellular immunity. In the current study, we sought to develop a novel anti-cancer agent as a complex of DNA and oncolytic adenovirus for the treatment of malignant melanoma in the C57BL/6 mouse model. MART1, a human melanoma-specific tumor antigen, was used to induce an increased immune reaction, since a MART1-protective response is required to overcome immune tolerance to the melanoma antigen MelanA. Because GM-CSF is a potent inducer of anti-tumor immunity and TGF-β2 is involved in tumor survival and host immune suppression, mouse GM-CSF (mGM-CSF) and shRNA of mouse TGF-β2 (shmTGF-β2) genes were delivered together with MART1 via oncolytic adenovirus. MART1 plasmid was also used for antigen-priming. To compare the anti-tumor effect of oncolytic adenovirus expressing both mGM-CSF and shmTGF-β2 (AdGshT) with that of oncolytic adenovirus expressing mGM-CSF only (AdG), each virus was intratumorally injected into melanoma-bearing C57BL/6 mice. As a result, mice that received AdGshT showed delayed tumor growth than those that received AdG. Heterologous prime-boost immunization was combined with oncolytic AdGshT and MART1 expression to result in further delayed tumor growth. This regression is likely due to the following 4 combinations: MART1-derived mouse melanoma antigen-specific immune reaction, immune stimulation by mGM-CSF/shmTGF-β2, tumor growth inhibition by shmTGF-β2, and tumor cell-specific lysis via an oncolytic adenovirus. Immune activation was mainly induced by mature tumor-infiltrating dendritic cell (TIDC) and lowered regulatory T cells in tumor-infiltrating lymphocytes (TIL). Taken together, these findings demonstrate that human MART1 induces a mouse melanoma antigen-specific immune reaction. In addition, the results also indicate that combination therapy of MART1 plasmid, together with an oncolytic adenovirus expressing MART1, mGM-CSF, and shmTGF-β2, is a promising candidate for the treatment of malignant melanoma.
Files in This Item:
T201700501.pdf Download
DOI
10.18632/oncotarget.15008
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Song, Jae Jin(송재진) ORCID logo https://orcid.org/0000-0001-8183-9550
Choi, Hye Jin(최혜진) ORCID logo https://orcid.org/0000-0001-5917-1400
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/154703
사서에게 알리기
  feedback

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse

Links