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Integration of High-Risk Human Papillomavirus DNA Is Linked to the Down-regulation of Class I Human Leukocyte Antigens by Steroid Hormones in Cervical Tumor Cells¹

Department of Immunology, Paterson Institute for Cancer Research, Christie Hospital, National Health Service Trust, Wilmslow Road, Manchester M20 4BX [J. S. B., S. G., D. J. B., J. C., P. L. S.], Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP [S. S., M. A. S.], United Kingdom; and Servicio de Analisis Clinicos, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Avda Fuerzas Armadas S/N, Granada, Spain [F. R-C., F. G.]

A crucial event in the malignant progression of cervical intraepithelial neoplasia appears to be the up-regulation of high-risk human papillomavirus (HPV) early gene expression. Steroid hormones have been linked to the progression from premalignant to neoplastic status in HPV positive lesions. This report demonstrates that at physiological levels, the glucocorticoid hormone hydrocortisone consistently down-regulates class I human leukocyte antigen (HLA) surface expression in HPV-positive cervical tumor cells but can up-regulate expression in HPV-negative epithelial tumor lines. Suppression of HLA expression was also seen with progesterone, another steroid hormone. The hydrocortisone-mediated modulation of HLA expression is dependent on integration and transcription of the HPV genome and can be blocked by Ru38486, an antagonist of both glucocorticoid and progesterone receptors, indicating the role of these receptors in mediating HLA suppression. The data suggest that HPV integration events in cervical epithelia correlate with hormone-dependent HLA suppression, possibly contributing to the avoidance of tumor recognition by cytotoxic T cells. These studies imply that clinical use of steroids may be contraindicated in HPV-positive individuals who have early premalignant cervical disease or neoplasia but provide evidence that the antiprogestin Ru38486 may be useful in the management of early stage cervical disease.

¹ This study received financial support from The Cancer Research Campaign (to J. S. B., S. G., D. J. B., and P. L. S.), the British Council (to J. C.), a Nehru fellowship (to S. S.), and Fondo de Investigaciones Sanitarias (to F. R. C. and F. G.).

² To whom requests for reprints should be addressed.

Received 8/ 5/96. Accepted 1/ 6/97.

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