NK-CELL ACTIVITY IN PATIENTS WITH HPV16-ASSOCIATED ANOGENITAL TUMORS - DEFECTIVE RECOGNITION OF HPV16-HARBORING KERATINOCYTES AND RESTRICTED UNRESPONSIVENESS TO IMMUNOSTIMULATORY CYTOKINES

Peripheral blood mononuclear cells (PBMC) from patients with active HP V16-associated pre-malignant and malignant anogenital lesions display a significantly decreased NK-cell activity against HPV16-harboring SKv keratinocytes (NK/SKv) while their cytotoxicity against erythroleukem ic K562 cells (NK/K562) remains unaffected. A similar defect can also be seen in some healthy individuals displaying no symptoms of HPV infe ction (low responders). Analysis with specific Leu IIa monoclonal anti bodies (MAbs) has revealed that all patients as well as weakly respond ing control subjects had normal numbers of circulating CD16+ NK cells. However, PBMC from patients with active disease and weakly responding controls displayed a significantly decreased ability to bind SKv cell s. Binding of K562 was in the normal range. In patients in whom the le sions were successfully removed or regressed spontaneously (patients w ith no lesions), NK/SKv activity did not differ from that of normally responding healthy subjects and the ability of their PBMC to bind SKv cells was unaffected. To determine whether an abrogated NK/SKv cytotox icity may be corrected by NK-cell stimulatory cytokines, PBMC were pre -incubated overnight with IL-2 and interferon-alpha. Both cytokines st imulated NK/K562 activity in all tested groups. Significant stimulatio n of NK/SKv activity was observed in PBMC from normal and weakly respo nding controls as well as patients with no lesions. No increase could be seen in patients with active disease. Evaluations of NK-cell activi ty before and after surgical removal or spontaneous regression of the lesions showed normalization of primarily depressed NK/SKv activity. M alignant progression was associated with a significant drop in SKv cel l killing. Our results suggest that abrogation of NK-cell activity aga inst HPV16-harboring targets in patients with HPV16-associated anogeni tal neoplasia is associated with restricted inability to recognize the disease-specific target cells, and may depend on persistence of the l esions. (C) 1993 Wiley-Liss, Inc.