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Disease-Stage Variance in Functional CD4⁺ T-Cell Responses Against Novel Pan-Human Leukocyte Antigen-D Region Presented Human Papillomavirus-16 E7 Epitopes

Departments of ¹ Immunology and ² Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; the ³ Magee-Womens Hospital Department of Obstetrics & Gynecology, Pittsburgh, Pennsylvania; the ⁴ Department of Obstetrics and Gynecology, University of Louisville, Louisville, Kentucky; the ⁵ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California; and the ⁶ Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

ABSTRACT

Given the anticipated clinical importance of helper and regulatory CD4⁺ T cells reactive against human papillomavirus-16 E7 in the cervical carcinoma setting, we performed this study to identify novel E7-derived T helper (Th) epitopes and to characterize functional anti-E7 Th responses in normal donors and patients with cervical intraepithelial neoplasia I-III or cervical cancer.

Candidate pan-HLA-DR (D region) binding peptides were identified and synthesized based on results obtained using a predictive computer algorithm, then applied in short-term in vitro T-cell sensitization assays. Using IFN-/IL-5 (interleukin 5) enzyme-linked immunospot assays as readouts for Th1-type and Th2-type CD4+ T-cell responses, respectively, we identified three E7-derived T helper epitopes (E7_1–12, E7_48–62, and E7_62–75), two of which are novel.

Normal donor CD4⁺ T cells failed to react against these E7 peptides, whereas patients with premalignant cervical intraepithelial neoplasia I-III lesions displayed preferential Th1-type responses against all three E7 epitopes. Th1-type responses were still observed to the E7_48–62 but not to the E7_1–12 and E7_62–75 peptides in cancer patients, where these latter two epitopes evoked Th2-type responses. Notably all responders to the E7_1–12 and E7_62–75 peptides expressed the HLA-DR4 or -DR15 alleles, whereas all responders to the E7_48–62 peptide failed to express the HLA-DR4 allele.

Our results are consistent with a model in which cervical cancer progression is linked to an undesirable Th1- to Th2-type shift in functional CD4⁺ T cell responses to two novel E7-derived epitopes. These peptides may prove important in vaccines to promote and maintain protective Th1-type antihuman papillomavirus immunity and in the immune monitoring of treated patients harboring HPV-16⁺ malignancies.

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