Abstract
Latent membrane protein 2A (LMP2A) is expressed on almost all Epstein–Barr virus (EBV)-associated tumors and is a potential target for immunotherapeutic intervention and vaccination. However, LMP2A is not efficiently processed and presented on major histocompatibility antigens class I molecules to generate potent cytotoxic T-lymphocytes (CTL) responses capable of killing these tumors. The B subunit of Escherichia coli enterotoxin (EtxB), causes rapid internalization and processing of membrane-bound LMP2A on EBV-infected B cells, and facilitates loading of processed-LMP2A peptides onto MHC class I. This re-directed trafficking/delivery of LMP2A to the MHC class I machinery enhances recognition and killing by LMP2A-specific CTL in vitro. To test the potential of EtxB to enhance immune targeting of LMP2A expressed in solid tumors, we generated a murine tumor model (Renca-LMP2A), in which LMP2A is expressed as a transgenic neoantigen on a renal carcinoma (Renca) cell line and forms solid tumors when injected subcutaneously into BALB/c mice. The data show that in BALB/c mice which have only low levels of peripheral Kd-LMP2A-specific CD8+ T cells, merely a transient inhibition of tumor growth is achieved compared with naïve mice; suggesting that there is suboptimal LMP2A-specifc CTL recognition and poorly targeted tumor killing. However, importantly, treatment of these mice with EtxB led to a significant delay in the onset of tumor growth and significantly lower tumor volumes compared with similar mice that did not receive EtxB. Moreover, this remarkable effect of EtxB was achieved despite progressive reduction in tumor expression of LMP2A and MHC class I molecules. These data clearly demonstrate the potential efficacy of EtxB as a novel therapeutic agent that could render EBV-associated tumors susceptible to immune control.
Highlights
The key to generating effective anti-cancer vaccines is the ability to stimulate cytotoxic T-lymphocytes (CTL) responses against tumor antigens [1, 2]
Wild type (WT) renal carcinoma (Renca) cells were transfected with the vector alone creating the Renca-VC cell line that served as a negative control for Renca-latent membrane protein 2A (LMP2A) cells
This resulted in a two-fold increase in the number of IFN-c+ CD8+ T cells compared with untreated Renca-LMP2A (Fig. 3C and D); clearly demonstrating that EtxB treatment of Renca-LMP2A can significantly enhance LMP2A-specific CTL responses, possibly by enhancing antigen processing and presentation in vitro
Summary
The key to generating effective anti-cancer vaccines is the ability to stimulate cytotoxic T-lymphocytes (CTL) responses against tumor antigens [1, 2]. For virus-associated cancers, CTL targeting of the viral antigens could potentially control tumor growth. Recent studies have shown that potent clinical responses may be achieved in certain patients with EBV-associated lymphomas by administering LMP2A-specific T cells or by vaccinating with LMP2A-transduced DC [5]. Despite such successes, there will be limitations with these types of a 2015 The Authors.
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