The B subunit of Escherichia coli enterotoxin helps control the in vivo growth of solid tumors expressing the Epstein–Barr virus latent membrane protein 2A

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.

Epstein-Barr virus BARF1-induced NFκB/miR-146a/SMAD4 alterations in stomach cancer cells

“…BARF1 has sequence homology with colony stimulating factor-1 receptor (hCSF1 receptor), and BARF1 binds to hCSF1 (macrophage-colony stimulating factor), similar to the binding between hCSF1 and hCSF1 receptor, which modulates the fates of immune-related cells such as macrophages [ 18 , 21 , 22 ]. EBV-encoded latent membrane protein (LMP) 2A is expressed on almost all EBV-positive human cancers [ 23 ], and the role of LMP2A in EBV-induced stomach carcinogenesis has been analyzed [ 6 , 10 , 24 , 25 ]. LMP1 is an established viral oncogene in EBV-infected malignant lymphoma and nasopharyngeal cancer [ 3 , 26 ]; however, LMP1 is not expressed in EBV-infected stomach cancer due to promoter methylation [ 3 , 6 , 10 ].…”