title: Immune escape phenotype of HPV16-associated tumours: MHC class I expression changes during progression and therapy.
abstract: Malignant transformation of somatic cells followed by selection of the transformed cell populations can give rise to tumours that display an immune escape phenotype, MHC class I deficient neoplasms. Experiments were designed to examine whether the immune escape phenotype of HPV16-associated tumours is stable or whether the MHC class I expression can change during tumour progression and therapy. It has been found that temporary growth of MHC class I- tumour MK16/1/IIIABC in syngeneic mice can lead to up-regulation of the low MHC class I expression, both in the subcutaneous tumour inocula and in their lung metastases. Mimicking this process in vitro by co-cultivation of tumour and spleen cell populations revealed that the spleen cells produce IFNgamma, which upregulates MHC class I expression on the MK16/1/IIIABC cells as well as their sensitivity to T cell-mediated cytolysis (CTLs). The up-regulation could be prevented by admixture of anti-IFNgamma antibody to the tumour/spleen cell mixtures. Similar up-regulation of the MHC class I expression was observed in HPV16-associated tumour cell lines, MK16/1/IIIABC, MK16/MET/M1, TC-1, TC-1/A9 and TC-1/P3C10 grown in vitro in the presence of IFNgamma. The up-regulation was found to be IFNgamma dose-dependent and the level of the MHC class I expression required for in vitro cytolysis of the tumour cells by CTLs could be characterized in cytofluorometry with anti-H-2 antibody. After removal of the IFNgamma from the cultivation medium or after injection of the IFNgamma-treated cells into syngeneic mice the MHC class I expression gradually dropped back to the original level or to the level observed on the tumours growing in vivo. These findings indicate that the immune escape phenotype of at least some HPV16-associated tumours is not stable and that up-regulation of the MHC class I expression can occur in vivo during progression of the MHC I- tumours, apparently due to production of IFNgamma by the immune cells in the tumour microenviroment and its vicinity. In vitro irradiation of HPV16-associated MHC class I-deficient tumour cell lines MK16/MET/M1 and TC-1/P3C10 with a dose of 150 Gy up-regulated their MHC class I expression. Similarly, substantial up-regulation of the MHC class I expression was observed in TC-1/A9 tumour recurrences after surgery. The up-regulation observed in the recurrences after surgery or after irradiation has reached the level required for in vitro cytolysis of the tumour cells by CTLs. If confirmed also with other tumour types and in human tumour systems, the up-regulation of MHC class I molecule expression during radiotherapy and in tumour recurrences after surgery may have important implications in the development of immunotherapeutic strategies.
authors.affiliation: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague 6, Czech Republic.
authors.forename: Romana
authors.initials: R
authors.lastname: Mikysková
authors.forename: Jan
authors.initials: J
authors.lastname: Bubeník
authors.forename: Vladimír
authors.initials: V
authors.lastname: Vonka
authors.forename: Michal
authors.initials: M
authors.lastname: Smahel
authors.forename: Marie
authors.initials: M
authors.lastname: Indrova
authors.forename: Jana
authors.initials: J
authors.lastname: Bieblová
authors.forename: Jana
authors.initials: J
authors.lastname: Símová
authors.forename: Tána
authors.initials: T
authors.lastname: Jandlová
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002860:Chromium Radioisotopes; D018920:Coculture Techniques; D018450:Disease Progression; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D005805:Genes, MHC Class I; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology* / Q000821:virology*; D009374:Neoplasms, Experimental; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis*; D027383:Papillomaviridae / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000276:immunology*; D010641:Phenotype; D012008:Recurrence; D013154:Spleen / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
chemical_list: D002860:Chromium Radioisotopes; D015395:Histocompatibility Antigens Class I; D009856:Oncogene Proteins, Viral; D007371:Interferon-gamma