Signaling defects in T lymphocytes of patients with malignancy

In patients with cancer, alterations in the expression of T-cell receptor-associated molecules in tumor-infiltrating lymphocytes (TIL) as well as in circulating lymphocytes have been reported. By quantitative flow cytometry analysis, decreased or absent expression of the zeta chain in CD4(+) or CD8(+) T cells as well as in natural killer (NK) cells was demonstrated in patients with malignancies. Changes in the expression of zeta are biologically significant, because the absence or low expression of this signaling molecule in TIL of patients with stage III or IV head and neck cancer predicts a significantly shorter 5-year survival than that of patients with normal zeta expression in TIL. Preliminary evidence indicates that expression of zeta in TIL may not only influence survival but also predicts a favorable response to biologic therapies. Patients with cancer also show significantly greater spontaneous ex vivo apoptosis in peripheral blood mononuclear cells (PBMC) compared to normal controls, as measured by a terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assay. While no correlation could be established between the proportions of cells with low zeta chain expression and those that spontaneously apoptose ex vivo, the zeta chain has been shown to be cleaved by caspases in T cells coincubated with tumor cells or with T cells exposed to CH-11 antibody, which induces apoptosis upon crosslinking Fas on the cell surface. The results suggest that low/absent zeta chain expression and lymphocyte apoptosis may be manifestations of negative effects of the tumor on the host immune system.