Signaling abnormalities, apoptosis, and reduced proliferation of circulating and tumor-infiltrating lymphocytes in patients with oral carcinoma

We have reported earlier that T cells found in the tumor microenvironment of head and neck cancer showed evidence of apoptosis as well as decreased expression of signaling molecules. In this prospective study, spontaneous apoptosis in tumor-infiltrating lymphocytes (TILs) and in paired circulating peripheral blood lymphocytes (PBLs) was evaluated in 28 patients with oral carcinoma and correlated with ζ-chain expression and anti-CD3 antibody-induced proliferation of the PBL obtained from each patient. In addition, expression of CD3, CD4, and CD8 molecules on TIL and Fas ligand (FasL) on the tumor was studied by immunohistochemistry. Soluble FasL was measured in the patients' sera. PBL obtained from 20 age-matched normal donors was used as a control. Reduced ζ-chain expression was observed in TIL-T of 9 of 28 patients and in PBL-T of 12 of 28 patients. Low ζ expression in autologous TIL-T and PBL-T was correlated (P < 0.0012), and it was associated with high levels of expression of FasL on the tumor (P = 0.0002 and P < 0.0013, respectively). Low ζ expression in PBL-T was also associated with the poor ability of these cells to proliferate in response to anti-CD3 antibodies (P = 0.0012). Increased proportions of apoptotic cells were detected in PBL of 6 of 28 (21%) patients versus 13 of 28 patients (46%) in TIL. Apoptosis in autologous PBL and TIL was found to correlate (P = 0.0322) and was significantly associated with reduced ζ-chain expression. Serum levels of soluble FasL were decreased in patients relative to normal controls but did not correlate with PBL apoptosis or FasL expression on the tumor. Decreased expression of TcR-associated ζ chain, depressed immune function, and apoptosis of T cells were observed to occur concomitantly in TIL and circulating PBL-T of a subset of patients with oral carcinoma. These alterations correlated with high levels of FasL expression on the tumor but not with the disease stage. The results suggest that tumor exerts systemic suppressive effects on immune cells, which may be, in part, mediated via the Fas/FasL pathway.