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

Autor: Jae J. Song, So Young Kim, Yeonsoo Joo, Hye Jin Choi, Dongxu Kang, Joo Hang Kim
Rok vydání: 2017
Předmět:
Zdroj: Oncotarget
ISSN: 1949-2553
DOI: 10.18632/oncotarget.15008
Popis: // So Young Kim 1, * , Dongxu Kang 1, 2, * , Hye Jin Choi 3 , Yeonsoo Joo 1, 4 , Joo-Hang Kim 5 , Jae J. Song 1, 4 1 Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea 2 Department of Oncology, Affiliated Hospital of Yanbian University, Yanji, Jilin Province, P.R. China 3 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea 4 Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea 5 CHA Bundang Medical Center, CHA University, Seongnam, Korea * These authors have contributed equally to this work Correspondence to: Joo-Hang Kim, email: kim123@cha.ac.kr Jae J. Song, email: jjs109@yuhs.ac Keywords: oncolytic adenovirus, MART1, DNA vaccine, GM-CSF, TGF-β2 Received: June 20, 2016 Accepted: December 31, 2016 Published: February 02, 2017 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 (Ad GshT ) with that of oncolytic adenovirus expressing mGM-CSF only (Ad G ), each virus was intratumorally injected into melanoma-bearing C57BL/6 mice. As a result, mice that received Ad GshT showed delayed tumor growth than those that received Ad G . Heterologous prime-boost immunization was combined with oncolytic Ad GshT 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.
Databáze: OpenAIRE
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