Experimental appraisal of the lack of antitumor natural killer cell—mediated immunosurveillance in response to lymphomas growing in the mouse brain

Abstract

Natural killer (NK) cell-mediated immunosurveillance in the brain is currently obscure, in contrast with the intracerebral immune reaction of cytotoxic T lymphocytes (CTLs) to tumor cells. The goal of this study, in which a controlled tumor model was used, was to investigate a relationship between NK cells and major histocompatibility complex (MHC) Class I gene expression in intracerebral tumor-bearing hosts. A matched set of two cloned tumor cell lines (lymphoma+ and lymphoma-), which differ only in MHC Class I gene expression, was established from the parental YAC-1 cell line (a target widely accepted as being sensitive to murine NK cells). An in vivo rapid elimination assay (REA) was performed using tumor cells labeled with [125I] 5-iodo-2-deoxyuridine to evaluate intracerebral NK cell-mediated defense immunity. There was no difference in the in vitro growth rate and c-myc gene expression between lymphoma+ and lymphoma- cells. An in vitro cytotoxicity assay showed that the lymphoma+ cell line was sensitive to MHC Class I-restricted CTL-mediated lysis, whereas the lymphoma- line was refractory to it. Both were susceptible to NK cell-mediated lysis, comparable to the level shown by YAC-1 cells. Flow cytometry revealed that lymphoma+ reacted positively for cell-surface MHC Class I molecules, whereas lymphoma- had no reaction. Four- to 72-hour REAs, performed using either cell line, disclosed no clearance of radiolabeled tumor cells from the brain in independent groups of untreated and T cell-depleted mice; this contrasted with eradication of radioactivity from the lungs. In NK cell-depleted mice, however, there was no elimination of radiolabeled tumor cells from the brain or lungs. The MHC Class I expression on lymphoma+ cells was enhanced after intracerebral inoculation, rendering them less sensitive to NK cells. By contrast, lymphoma- cells remained negative for cell-surface MHC expression, being sensitive to NK cells and refractory to CTLs after intracerebralinoculation. These results indicate the absence of NK cell-mediated lytic activity in the brain. This allows even NK cell-sensitive tumor cells to escape intracerebral immunosurveillance. These experiments have refined the information that the brain may lack NK cell-mediated defense immunity against intracerebrally growing tumors, representing a characteristic aspect of this immunologically privileged organ.