Control of spontaneous ovarian tumors by CD8+ T cells through NKG2D-targeted delivery of antigenic peptide
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RESEARCH
Cell & Bioscience Open Access
Control of spontaneous ovarian tumors by CD8+ T cells through NKG2D-targeted delivery of antigenic peptide Tae Heung Kang1, Jayne Knoff2, Benjamin Yang2, Ya-Chea Tsai2, Liangmei He2, Chien-Fu Hung2,4 and T-C Wu2,3,4,5*
Abstract 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. Keywords: NKG2D, Ovarian cancer, Immunotherapy, T cell adoptive transfer, TgMISIIR-TAg transgenic mice
Background Advanced ovarian cancer is one of the most deadly malignancies and is responsible for the highest mortality rate among patients with cancers of the female reproductive system in the United States. Existing therapies for ovarian cancer, such as surgery and chemotherapy, have significant side effects and rarely result in long-term cures for patients with locally advanced or metastatic disease, although they can provide remission for several years [1,2]. The lack of * Correspondence: [email protected] 2 Department of Pathology, School of Medicine, Johns Hopkins University, Bldg. CRBII Rm. 309, 1550 Orleans Street, Baltimore, Maryland 21231, USA 3 Department of Obstetrics and Gynecology, Johns Hopkins University, Baltimore, MD 21205, USA Full list of author information is available at the end of the article
curative treatments
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