Induction of a specific CD8+ T-cell response to cancer/testis antigens by demethylating pre-treatment against osteosarcoma

Abstract

// Binghao Li 1 , Xiaobing Zhu 2 , Lingling Sun 1 , Li Yuan 3 , Jian Zhang 1 , Hengyuan Li 1 , Zhaoming Ye 4 1 Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310008, China 2 Department of Orthopaedics, Taizhou Cancer Hospital, Taizhou, 317502, China 3 School of Public Health, Fudan University, Shanghai, 200032, China 4 Centre for Orthopaedic Research, Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310008, China Correspondence to: Zhaoming Ye, e-mail: yezhaominghz@163.com Keywords: Osteosarcoma, Adoptive immunotherapy, Cancer/testis antigens, Demethylating treatment, Combination therapy Received: August 5, 2014      Accepted: September 16, 2014      Published: October 04, 2014 ABSTRACT Conventional non-surgical therapeutic regimens against osteosarcoma are subject to chemoresistance and tumor relapse, and immunotherapy may be promising for this tumor. However, it’s hard to find satisfactory epitopes for immunotherapy against osteosarcoma. Cancer/testis antigens (CTAs), such as MAGE-A family and NY-ESO-1, the potential antigens that almost exclusively express in tumor cells and immune-privileged sites, have been found expressed in osteosarcoma also. Nevertheless, the expression of CTAs is downregulated in many tumors, constraining the application of immunotherapy. In this article, we demonstrate that the expression of MAGE-A family and NY-ESO-1 in osteosarcoma cells can be upregulated following treatment with demethylating agent 5-aza-2′-deoxycytidine and consequently induces a CTA specific CD8+ T-cell response against osteosarcoma in vitro and in vivo . The in vivo imaging was realized by using luciferase-transfected HOS cells and DiR labeled T-cells in severely combined immunodeficiency mouse models. Cytotoxic T cells specifically recognizing MAGE-A family and NY-ESO-1 clustered at the tumor site in mice pre-treated with DAC and resulted in tumor growth suppression, while it was not observed in mice without DAC pre-treatment. This study is important for more targeted therapeutic approaches and suggests that adoptive immunotherapy, combined with demethylating treatment, has the potential for non-surgical therapeutic strategy against osteosarcoma.