title: Cytokeratin 8-MHC class I interactions: a potential novel immune escape phenotype by a lymph node metastatic carcinoma cell line.
abstract: Defective human leukocyte antigen (HLA) class I expression in malignant cells facilitates their escape from destruction by CD8(+) cytotoxic T lymphocytes. In this study, a post-translational mechanism of HLA class I abnormality that does not involve defects in the HLA subunits and antigen processing machinery components was identified and characterized. The marked HLA class I downregulation phenotype of a metastatic carcinoma cell line can be readily reversed by trypsin, suggesting a masking effect by serine protease-sensitive HLA class I-interacting factors. Co-immunoprecipitation, combined with LC-tandem mass spectrometry and immunoblotting identified these factors as cytokeratin (CK) 8 and its heterodimeric partners CK18 and CK19. Ectopic CK8/18 or CK8/19 expression in HEK293 cells resulted in surface CK8 expression with an HLA class I downregulation phenotype, while redirecting CK8/18 and CK8/19 to the endoplasmic reticulum (ER) had no such effect. This observation and the failure to constrain CK8/18 and CK8/19 membrane trafficking by an ER-Golgi transport inhibitor suggested an ER-independent route for CK8 access to HLA class I molecules. Monoclonal antibody mapping revealed a potential CK8 blockade of HLA class I-CD8 and -TCR contacts. These findings, along with the emerging role of cell surface CK8 in cancer metastasis, may imply a dual strategy for tumor cell survival in the host.
authors.affiliation: Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Ming-Syue
authors.initials: MS
authors.lastname: Wu
authors.forename: Chia-Hsuan
authors.initials: CH
authors.lastname: Li
authors.forename: Jan Gustav
authors.initials: JG
authors.lastname: Ruppert
authors.forename: Chien-Chung
authors.initials: CC
authors.lastname: Chang
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal; D002277:Carcinoma / Q000556:secondary*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D047468:Immunoprecipitation; D053538:Keratin-18; D053539:Keratin-19; D053533:Keratin-8 / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008207:Lymphatic Metastasis / Q000276:immunology*; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D014357:Trypsin / Q000276:immunology; D019139:Tumor Escape
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D053538:Keratin-18; D053539:Keratin-19; D053533:Keratin-8; D014357:Trypsin
keywords: Cytokeratin; Human leukocyte antigen; Tumor immune escape