Frequency of down-regulation of individual HLA-A and -B alleles in cervical carcinomas in relation to TAP-1 expression

Abstract

Summary The development of cervical carcinoma is strongly associated with specific types of human papillomaviruses (HPVs). A role for cellular immunity in cervical disease is supported by the increased occurrence of HPV-associated lesions in immunosuppressed individuals. Upon viral infection or malignant transformation, ensuing alterations in gene expression result in the generation of novel sets of peptides which can form complexes with specific HLA class I heavy chains and P2-microglobulin. These are then expressed at the cell surface as potential targets for specific T cells. In this study of 100 carcinomas HLA-A and -B class I expression by the tumour cells was down-regulated at one or more alleles in at least 73% of cervical carcinomas. Interference with the transporter associated with antigen presentation (TAP), which translocates cytosolic peptides from endogenously synthesised proteins (e.g. viral) into the lumen of the endoplasmic reticulum was found in 38% of the HLA class I down-regulated tumours. Loss of expression for common HLA class I alleles ranged from 36% to 71%, and such changes might be expected to influence specific immunogenic peptide presentation and consequent immune recognition. These results underline the importance of single as well as multiple allelic loss in cervical neoplasia and have important implications for attempts to intervene immunologically in cervical cancer.

Transcriptional regulation of the major histocompatibility complex (MHC) class I heavy chain, TAP1 and LMP2 genes by the human papillomavirus (HPV) type 6b, 16 and 18 E7 oncoproteins

“…Loss of MHC class I molecules is a frequent event in both premalignant and malignant cervical lesions (Connor and Stern, 1990;Cromme et al, 1993a,b) and loss of the peptide transporter subunit TAP1 has also been found in malignant and metastatic lesions (Cromme et al, 1994b;Keating et al, 1995). It appears that there is no clear correlation between the presence of HPV DNA, or HPV 16 E7 transcripts and the MHC phenotype in cervical lesions (Bartholomew et al, 1995;Cromme et al, 1993b).…”

“…Complete or heterogeneous loss of class I molecules associated with loss of TAP1 expression has been demonstrated (Cromme et al, 1994a;Keating et al, 1995), whereas a signi®cant increase in class I downregulation, accompanied by loss of TAP1 expression, was observed in metastatic cells in comparison to primary tumours (Cromme et al, 1994b). Transcriptional repression of other major components of the antigen presentation pathway by Ad 12 has been reported.…”

Assessment of cytotoxic T-lymphocyte phenotype using the specific markers granzyme B and TIA-1 in cervical neoplastic lesions

“…An active role for the cellular immune system in the prevention of the development of cervical cancer is evidenced by a higher incidence of HPV-associated premalignant lesions in immunocompromised patients, such as AIDS patients and transplant recipients (Halpert et al, 1986;Laga et al, 1992). However, we and others have shown that major histocompatibility complex (MHC) class I expression is frequently down-regulated on neoplastic cells in malignant and premalignant lesions (Connor and Stem, 1990;Cromme et al, 1993;Honma et al, 1994;Keating et al, 1995). Lower expression or even complete absence of MHC class I molecules on tumour cells could affect their lysis by cytotoxic T cells as has been shown in melanomas (Rivoltini et al, 1995).…”

Metastatic MHC class I-negative mouse cells derived by transformation with human papillomavirus type 16

“…Because of the latter two characteristics, MK16/1/IIIABC cells may serve as a highly suitable model for studying immune reactions against HPV16-associated human tumours. It should be remembered that in about 70% of CC the production of MHC class I molecules is downregulated and these patients have a worse prognosis (Connor et al, 1993;Keating et al, 1995). It has also been reported that MHC class I expression in metastases is lower than in primary tumours (Cromme et al, 1994).…”