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Lymphocytes recovered from human tumors or peripheral circulation of patients with advanced cancer have abnormalities in signaling via the T cell receptor (TcR) or FcγRIII. Here we show that in comparison with normal T lymphocytes, those isolated from tumor-involved lymph nodes (LNLs) or blood (PBLs) of patients with head and neck carcinoma (HNC) have a variety of defects in expression and function of signaling molecules, including significantly decreased expression of TcR-associated ξ and ε chains, decreased Ca2+ flux, as well as impaired kinase activity following triggering with anti-CD3 antibodies and altered expression of downstream protein tyrosine kinase p56lck. Some of these alterations were demonstrable not only in isolated LNLs or PBLs but also in situ in patients' biopsies. Expression of mRNA for the ξ chain in LNLs was comparable with that seen in normal T cells. Significantly, LNLs of patients with HNC were shown to contain numerous apoptotic, TUNEL+ [TdT-mediated dUTP nick-enol labelling] cells in situ. Co-expression of CD3-ε+ and TUNEL+ in the same cells in situ was observed. Co-incubation of normal activated T cells or Jurkat cells with HNC cell lines induced apoptosis in a substantial proportion of lymphocytes. HNC cell lines and HNC in situ were shown to express FasL, while LNLs in tumor-involved lymph nodes were Fas+. These data suggest that signaling defects, which are commonly found in lymphocytes of HNC patients, might be a part of the process of apoptosis induced by the tumor in lymphocytes found in its milieu.