Control of spontaneous ovarian tumors by CD8 T cells through NKG2D-targeted delivery of antigenic peptideReportar como inadecuado




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Cell and Bioscience

, 3:48

First Online: 20 December 2013Received: 04 November 2013Accepted: 14 November 2013

Abstract

BackgroundThere 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.

ResultsWe 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.

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

KeywordsNKG2D Ovarian cancer Immunotherapy T cell adoptive transfer TgMISIIR-TAg transgenic mice AbbreviationsRFurin cleavage site

CTLCytotoxic T lymphocyte

MesoMesothelin

ScFvSingle chain variable fragment

OVAO – ovalbumin

MHCMajor histocompatibility complex

MOVCARMouse ovarian carcinoma cell line

OT-1OVA-specific CD8+ T cells

MISIIRMüllerian inhibiting substance type II receptor

FSHRFollicle-stimulating hormone receptor

ICAM-1Intercellular adhesion molecule 1

HER2Human epidermal growth factor receptor 2.

Electronic supplementary materialThe online version of this article doi:10.1186-2045-3701-3-48 contains supplementary material, which is available to authorized users.

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Autor: Tae Heung Kang - Jayne Knoff - Benjamin Yang - Ya-Chea Tsai - Liangmei He - Chien-Fu Hung - T-C Wu

Fuente: https://link.springer.com/







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