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.
Highlights
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
We showed that meso-scFv preferentially delivered O – ovalbumin (OVA) to mesothelin-expressing ovarian cancer cells, where cleavage by furin released the foreign immunogenic Cytotoxic T lymphocyte (CTL) epitope to be loaded on Major histocompatibility complex (MHC) class I molecules of tumor cells [4]
We showed that ovarian tumor cells that express the NKG2D ligand Rae-1 can be bound by the chimeric NKG2D-Fc-RO protein and present the OVA CTL peptide through MHC class I molecules
Summary
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. The cargo domain of the therapeutic chimeric protein was comprised of the Fc portion of the IgG2a protein and a MHC class I-restricted foreign immunogenic CTL epitope, OVA, flanked by furin cleavage sites. We showed that meso-scFv preferentially delivered OVA to mesothelin-expressing ovarian cancer cells, where cleavage by furin released the foreign immunogenic CTL epitope to be loaded on MHC class I molecules of tumor cells [4]. This rendered tumor cells susceptible to OVA-specific CTL-mediated killing, both in vitro and in vivo [4]. The encouraging results from these studies in the ovarian tumor model warrant further exploration of the molecular targets expressed by tumors for our therapeutic approach
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