CTL Control of EBV in Nasopharyngeal Carcinoma (NPC): EBV-Specific CTL Responses in the Blood and Tumors of NPC Patients and the Antigen-Processing Function of the Tumor Cells

Abstract

Undifferentiated nasopharyngeal carcinoma (NPC) is latently infected with EBV and expresses a restricted number of viral proteins. Studies in healthy virus carriers have demonstrated that at least some of these proteins can act as targets for HLA class I-restricted CTLs. Therefore we have explored the possibility of a CTL-based therapy for NPC by characterizing EBV-specific CTL responses in 10 newly diagnosed NPC cases and 21 healthy virus carriers from Southeast Asia. Using the autologous EBV-transformed lymphoblastoid cell line, virus-specific CTL were reactivated in vitro from PBMC, cloned, and screened for cytotoxicity against target cells expressing individual EBV proteins from recombinant vaccinia vectors. EBV-specific CTLs were identified in 6 of 10 patients and 14 of 21 controls and mainly targeted the EBV nuclear Ag 3 (EBNA3) family of viral latent proteins. However, in 3 of 10 patients and 11 of 21 controls, CTLs specific for the NPC-associated protein LMP2 were also detected, albeit at low frequency. EBV-specific CTLs were detected in tumor biopsy material obtained from 3 of 6 of the patients, indicating that functional CTL are present at the tumor site, but none was specific for tumor-associated viral proteins. To assess the Ag-presenting function in NPC we studied two NPC-derived cell lines (C15 and c666.1) and demonstrated that both were capable of processing and presenting endogenously synthesized protein to HLA class I-restricted CTL clones. Overall, our data provide a sound theoretical basis for therapeutic strategies that aim to boost or elicit LMP2-specific CTL responses in NPC patients.

Potent Dendritic Cell Vaccine Loaded with Latent Membrane Protein 2A (LMP2A)

“…To date, conventional approaches for the treatment of EBVrelated malignancies are often not curative or associated with serious complications. New immunotherapeutic strategies, such as adoptive transfer of CTLs or mAbs, may be effective if the tumor cells express immunodominant proteins (25,27,38). HD, BL, and NPC cancers appeared to be less susceptible to immunotherapeutic intervention, presumably due to the expression of a more restricted array of subdominant EBV-encoded epitopes derived from latent proteins (EBNA1, LMP1, and LMP2) (19,20).…”

“…NPC patients possessed CTL precursors specific for EBV-LMP2 and EBV-specific T cell responses were detectable in patients, albeit at lower levels than in healthy controls (26,27). The point was whether they included responses to those viral proteins expressed in the tumor.…”

Expression of immune-related molecules in primary EBV positive chinese nasopharyngeal carcinoma: Associated with latent membrane protein 1 (LMP1) expression

“…25 However, it has also been demonstrated that EBV positive NPC tumor cells could be recognized by autologous EBV specific CTLs in vitro; and the antigen proceeding and presenting system is intact in NPC tumor cell lines in previous research. 60,61 These founding provide the possibility of success for immunotherapy in some NPC patients who have intact antigen proceeding and presenting systems in tumor cells. However, it is necessary to examine the expressions of immune-molecules in tumor lesions, which will influence the outcome of T-cell-based adoptive immunotherapy.…”

Identification and prevalence of CD8+ T‐cell responses directed against Epstein‐Barr virus‐encoded latent membrane protein 1 and latent membrane protein 2

“…27,28 However, these tumors show patterns of viral antigen expression, which appear to be limited to EBNA1, LMP1 and LMP2. Since endogenously expressed EBNA1 is protected from presentation via the HLA class I pathway, attempts to target these tumors with EBV-specific CTLs depend upon the ability to boost responses to LMP1 and LMP2.…”