ANATOMIC PATHOLOGY Original Article The Expression of Histocompatibility-related Leukocyte Antigens in the Pathway to Cervical Carcinoma CARINA G.J.M. HILDERS, MD, 1 JOS G.A. HOUBIERS, MD, 2 EVELINE J.T. KRUL, MD, 1 AND GERT JAN FLEUREN, MD, PHD 1 The major histocompatibility complex probably plays a crucial role in the efficacy of the cellular immune response against virally infected cervical diseases. Therefore, the allelc-spccific histocoinpatibilit}-re- lated leukocyte antigens (HLA) class I and II expression on normal (n = 10), premalignant (n = 25), and malignant cervical tissue (n = 30) was investigated. No alterations in monomorphic or locus/allele-spe- ciflc III A class I or II expression were observed in normal and prema- lignant epithelial tissue. In cervical carcinomas, however, a reduced expression of HLA class I antigens was present in 70% of the cases, comprising a monomorphic class I loss in 20%, and an allele-specific loss in 50% of HLA-A2-, 66% of A3-, 56% of Bw4-, and 37% of Bw6-positive patients. De novo expression of class II antigens was ob- served in 80% of the cervical carcinomas, with the sublocus products being expressed in the order HLA-DR > HLA-DQ > HLA-DP. The authors' results show that alteration in HLA expression is a process confined to malignant cells, which may allow tumors to evade immune surveillance. In addition, these findings have to be considered as new strategies of immunotherapy using cytoto.xic T lymphocytes are devel- oped. (Key words: Allele-specific loss; Cervix; HLA antigens) Am J ClinPathol 1994;101:5-l 2. The histocompatibility-related leukocyte antigens (HLA) class I and II of the major histocompatibility complex represent mol- ecules that play an important role in antigen presentation, cy- totoxic response, and immune recognition. 1 In vivo, levels of HLA class I and II antigens on cells of a given type can differ as a consequence of disease, 2 - 3 differentiation state, 4 or stimula- tion by cytokines, 5 or as a result of malignant transformation. 6 In cervical tissue, several studies have been reported on the monomorphic HLA class I and II expression on normal and premalignant cells 7 " 10 and on alterations in HLA expression on cervical carcinoma cells. 7 "" 13 Changes in HLA class I and II expression can directly affect the immunogenicity of the tumor cells by interfering with im- munosurveillance. 14 ' 15 Specifically, in human papillomavirus- related cervical tumor tissue, 16 in which the virus antigen proba- bly serves as a tumor-specific antigen, the recognition by cytotoxic T cells might play a crucial role. Individual HLA alíeles act as restriction elements in presenting tumor-specific antigens to cytotoxic T lymphocytes. Presumably, alterations in HLA expression, whereby the cellular immunorecognition system cannot detect and eliminate virally transformed cells, involve allele-specific changes in class I expression. Most stud- ies of HLA expression on cervical tissue have been performed with monomorphic class I and II antibodies, which do not dif- From the Departments op Pathology and 2 Surgery, University of Lei- den, The Netherlands. Manuscript received August 25, 1992; revision accepted December 21, 1992. Address reprint requests to Dr. Hilders: Department of Pathology. University of Leiden. P.O. Box 9603. 2300 RC Leiden, The Nether- lands. ferentiate between the products of the individual HLA class I loci, A, B, C, their allelic forms, and the DR, DP, DQ products of HLA class II. Two studies on specific class I and II alter- ations on cervical tumor tissue revealed changes in allele-spe- cific HLA expression. 1113 To investigate whether selective changes in HLA class I and II expression occur in the progression of early stages of cervical intraepithelial neoplasia to cervical carcinoma, we focused on the allele-specific expression of HLA antigens in normal, pre- malignant, and malignant cervical tissue. We used a panel of monoclonal antibodies directed against the A-locus (A2 and A3 alíeles) and the B-locus (Bw4 and Bw6 alíeles) HLA class I products, and the expression of DR, DP, and DQ for HLA class II products. This allowed us to differentiate between the prod- ucts of the individual HLA class I and class II genes. Our data suggest that alterations in HLA expression are con- fined to malignant cells, with frequent alterations in allele-spe- cific class I expression. MATERIALS AND METHODS Tissue Samples and Preparation Samples of normal cervical tissue (n = 10), cervical intra- epithelial neoplasia (n = 25), and squamous cell carcinomas of the cervix (n = 30) were supplied by the Departments of Pathol- ogy and Gynecology of Leiden University Hospital and the Departments of Pathology and Gynecology of Leyenburg Hos- pital, The Hague. All the samples were obtained before treat- ment. The tissue was snap-frozen in liquid isopentane and stored at —70 °C until sectioned for study. Downloaded from https://academic.oup.com/ajcp/article/101/1/5/1755013 by guest on 01 May 2023