The Fas Counterattack In Vivo: Apoptotic Depletion of Tumor-Infiltrating Lymphocytes Associated with Fas Ligand Expression by Human Esophageal Carcinoma

• Published in: The Journal of immunology (1950) 1998-06, Vol.160 (11), p.5669-5675
• Main Authors: Bennett, Michael W, O'Connell, Joe, O'Sullivan, Gerald C, Brady, Ciaran, Roche, Desmond, Collins, J. Kevin, Shanahan, Fergus
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - immunology; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Apoptosis - immunology; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Esophageal Neoplasms - immunology; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Fas Ligand Protein; fas Receptor - metabolism; Humans; Immunohistochemistry; Ligands; Lymphocyte Depletion; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - pathology; Membrane Glycoproteins - biosynthesis
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.160.11.5669

Various cancer cell lines express Fas ligand (FasL) and can kill lymphoid cells by Fas-mediated apoptosis in vitro. FasL expression has been demonstrated in several human malignancies in vivo. We sought to determine whether human esophageal carcinomas express FasL, and whether FasL expression is associated with increased apoptosis of tumor-infiltrating lymphocytes (TIL) in vivo, thereby contributing to the immune privilege of the tumor. Using in situ hybridization and immunohistochemistry, respectively, FasL mRNA and protein were colocalized to neoplastic esophageal epithelial cells in all esophageal carcinomas (squamous, n = 6; adenocarcinoma, n = 2). The Extent of FasL expression was variable, with both FasL-positive and FasL-negative neoplastic regions occurring within tumors. TIL were detected by immunohistochemical staining for the leukocyte common Ag, CD45. FasL expression was associated with a mean fourfold depletion of TIL when compared with FasL-negative areas within the same tumors (range 1.6- to 12-fold, n = 6,p < 0.05). Cell death of TIL was detected by dual staining of CD45 (immunohistochemistry) and DNA strand breaks (TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling). There was a mean twofold increase in detectable cell death among TIL in FasL-positive areas compared with FasL-negative areas (range 1.6- to 2.4-fold, n = 6, p < 0.05). In conclusion, we demonstrate a statistically significant, quantitative reduction of TIL concomitant with significantly increased TIL apoptosis within FasL-expressing areas of esophageal tumors. Our findings suggest Fas-mediated apoptotic depletion of TIL in response to FasL expression by esophageal cancers, and provide the first direct, quantitative evidence to support the Fas counterattack as a mechanism of immune privilege in vivo in human cancer.