Emergence of non-major-histocompatibility-complex-restricted lytic CD8+ cells in the blood of nasopharyngeal carcinoma patients

Abstract

A large body of evidence has suggested that the Epstein-Barr virus (EBV) is strongly associated with undifferentiated nasopharyngeal carcinoma. Immunologically, this neoplasia is characterized by the absence of anti-EBV circulating cytotoxic T lymphocytes (CTL), despite a high number of peripheral activated CD8+ cells, as previously determined in our laboratory. In order to determine whether the absence of anti-EBV CTL is related to a reduced number of circulating anti-EBV effector cells, we attempted to expand these hypothetical specific T cells by induction of proliferation with recombinant interleukin-2 (rIL-2), in the, absence of any stimulator cells. Optimal conditions for stimulation of peripheral blood lymphocytes (PBL) of nasopharyngeal patients were obtained with 100 U/ml rIL-2 during 10 days of culture. PBL treated with rIL-2 induced a selective expansion of CD8+ cells and generated a potent cytotoxicity towards autologous or HLA-compatible lymphoblastoid cell lines, used as target cells in a chromium-release thest. However, this cytolysis was non-MHC-restricted, since, the monoclonal antibodies anti-(HLA class I) and anti-(HLA class II) were inefficient in inhibiting this cytotoxicity. Interestingly, purified CD8+ cells acquired the capacity for non-MHC-restricted cytolysis.

Cytokine and immunoglobulin production by PWM-stimulated peripheral and tumor-infiltrating lymphocytes of undifferentiated nasopharyngeal carcinoma (NPC) patients

“…Previous reports indicate the absence of EBV-specific cytotoxic T lymphocytes detectable by the standard chromium release assay in both the peripheral and intratumoral compartments [8-10,21] in undifferentiated nasopharyngeal carcinoma. However, NPC patients show a strong EBV-specific humoral immune response, and elevated titers of anti-EBV antibodies directed against viral antigens are observed in their sera [11,12,24].…”

“…The majority of the isolated CTL clones are directed towards the most immunogenic EBNA3 proteins which are not expressed in NPC tumor cells. No EBV-specific CTL activity is detectable by the standard chromium release assay in NPC patients [8-10] and the activity of any CTLs that would be present in such patients appears to be somehow suppressed. This lack of cytotoxic activity is in sharp contrast with the strong anti-EBV humoral immune response seen in patients [11,12].…”

“…These authors suggested IL-10 as a possible evasion mechanism against the host antiviral system. Such a mechanism would explain the lack of detection of EBV specific cytotoxic activity in NPC patients at both peripheral and intratumoral levels [8-10,21]. Indeed, IL-10 is known to inhibit cell-mediated immune responses [22].…”