Control of spontaneous ovarian tumors by CD8+ T cells through NKG2D-targeted delivery of antigenic peptide

Cell & Bioscience

T-C Wu⁴  Chien-Fu Hung³  Liangmei He²  Ya-Chea Tsai²  Benjamin Yang²  Jayne Knoff²  Tae Heung Kang¹ 

[1] Department of Immunology, College of Medicine, Konkuk University, Chungju, South Korea;Department of Pathology, School of Medicine, Johns Hopkins University, Bldg. CRBII Rm. 309, 1550 Orleans Street, Baltimore, Maryland 21231, USA;Department of Molecular Microbiology and Immunology, Johns Hopkins University, Baltimore, MD 21205, USA;Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA

关键词: TgMISIIR-TAg transgenic mice;    T cell adoptive transfer;    Immunotherapy;    Ovarian cancer;    NKG2D;   

Others  :  791389
DOI  :  10.1186/2045-3701-3-48

 received in 2013-11-04, accepted in 2013-11-14,  发布年份 2013

【 摘 要 】

Background

There is an urgent need to develop targeted therapies for the control of advanced stage ovarian cancer because it is the most deadly gynecologic cancer. Antigen-specific immunotherapy is a promising approach because of the potential of the immune system to specifically target tumors without the toxicity associated with traditional chemoradiation. However, one of the major limitations for antigen-specific cancer immunotherapy is the pre-existing immune tolerance against endogenous targeted tumor antigens that frequently evolves during carcinogenesis. Here, we described the creation of a therapeutic agent comprised of a tumor-homing module fused to a functional domain capable of selectively rendering tumor cells sensitive to foreign antigen-specific CD8+ T cell-mediated immune attack, thereby circumventing many aspects of immune tolerance. The tumor-homing module, NKG2D, specifically binds to NKG2D ligand that is commonly overexpressed in ovarian tumors. The functional domain is comprised of the Fc portion of IgG2a protein and foreign immunogenic CD8⁺ T cell epitope flanked by furin cleavage sites (R), which can be recognized and cleaved by furin that is highly expressed in the tumor microenvironment.

Results

We show that this therapeutic chimeric protein specifically loaded antigenic epitope onto the surface of NKG2D ligand-expressing ovarian tumor cells, rendering ovarian tumors susceptible to antigen-specific CTL-mediated killing in vitro. Furthermore, we show that intraperitoneal administration of our therapeutic chimeric protein followed by adoptive transfer of antigen-specific CD8+ T cells generates potent antitumor effects and significant accumulation of antigen-specific CD8+ T cells in the tumor loci.

Conclusions

Our findings have promise for bypassing immune tolerance to enhance cancer immunotherapy.

【 授权许可】

   
2013 Kang et al.; licensee BioMed Central Ltd.

【 图 表 】

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