Detection of human papillomavirus (HPV) 16-specific CD4+ T-cell immunity in patients with persistent HPV16-induced vulvar intraepithelial neoplasia in relation to clinical impact of imiquimod treatment

Purpose: Topical application of the immune response modifier imiquimod is an alternative approach for thetreatment of human papillomavirus (HPV)-positive vulvar intraepithelial neoplasia (VIN) and aims at the immunologic eradication of HPV-infected cells. We have charted HPV16-specific immunity in 29 patients with high-grade VIN and examined its role in the clinical effect of imiquimod treatment. Experimental Design: The magnitude and cytokine polarization of the HPV16 E2-, E6-, and E7-specific CD4+ T-cell response was charted in 20 of 29 patients by proliferation and cytokine bead array. The relation between HPV16-specific type 1T-cell immunity and imiquimod treatment was examined in a group of 17 of 29 patients. Results: HPV16-specific proliferate responses were found in 11 of the 20 patients. In eight of these patients, T-cell reactivity was associated with IFNγ production. Fifteen of the women treated with imiquimod were HPV16+, of whom eight displayed HPV16 E2- and E6-specific T-cell immunity before treatment. Imiquimod neither enhanced nor induced such immunity in any of the subjects. Objective clinical responses (complete remission or >75% regression) were observed in 11 of the 15 patients. Of these 11 responders, eight patients displayed HPV16-specific type 1CD4+ T-cell immunity, whereas three lacked reactivity. Notably, the four patients without an objective clinical response also lacked HPV16-specific type 1T-cell immunity. Conclusions: HPV16-specific IFNγ-associated CD4+ T-cell immunity, although not essential for imiquiimod-induced regression of VIN lesions, may increase the likelihood of a strong clinical response (P = 0.03).

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