title: Signaling abnormalities, apoptosis, and reduced proliferation of circulating and tumor-infiltrating lymphocytes in patients with oral carcinoma.
abstract: 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 zeta-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 zeta-chain expression was observed in TIL-T of 9 of 28 patients and in PBL-T of 12 of 28 patients. Low zeta 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 zeta 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 zeta-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 zeta 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.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Mainz, 55131 Mainz, Germany.
authors.forename: Torsten E
authors.initials: TE
authors.lastname: Reichert
authors.forename: Laura
authors.initials: L
authors.lastname: Strauss
authors.forename: Eva M
authors.initials: EM
authors.lastname: Wagner
authors.forename: William
authors.initials: W
authors.lastname: Gooding
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000473:pathology*; D002455:Cell Division; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000276:immunology / Q000473:pathology*; D010641:Phenotype; D011446:Prospective Studies; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology*
chemical_list: D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain