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Antitumor Activity of Human Papillomavirus Type 16 E7–Specific T Cells against Virally Infected Squamous Cell Carcinoma of the Head and Neck

Departments of ¹ Pathology, ² Otolaryngology, ³ Immunology, and ⁴ Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and ⁵ Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Robert L. Ferris, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Research Wing, Room 1.19d, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: 412-623-7738; Fax: 412-623-1415; E-mail: ferrisrl{at}upmc.edu.

Human papillomavirus (HPV)–associated squamous cell carcinoma of the head and neck (SCCHN) seems to be a suitable target for cancer vaccination. HPV-encoded oncogenic proteins, such as E7, are promising tumor-specific antigens and are obligatory for tumor growth. Because few immunologic studies have analyzed the endogenous HPV-specific immune response in this subset of SCCHN patients, we studied T-cell frequencies against HPV-16 E7_11-20 or E7_86-93 in tumor-bearing, human leukocyte antigen (HLA)-A*0201⁺ SCCHN patients, whose tumors were either HPV-16⁺ or HPV-16^–. In HPV-16⁺ SCCHN patients, frequencies of T cells against either peptide were significantly elevated (P < 0.005) compared with HPV-16^– patients or healthy volunteers. Tetramer⁺ T cells showed evidence of terminally differentiated phenotype (CD45RA⁺CCR7^–) and an elevated level of CD107a staining for degranulation. Despite detectable expression of the restricting HLA class I allele, HLA-A*0201-E7_11-20– or HLA-A*0201-E7_86-93–specific CTL obtained by in vitro stimulation of healthy donor peripheral blood mononuclear cells only recognize a naturally HPV-16-transformed, HLA-A*0201⁺ SCCHN cell line after pretreatment with IFN-. This cell line had little or no expression of LMP2, TAP1, and tapasin, critical components of the HLA class I antigen-processing machinery, which were up-regulated by IFN- treatment. Immunohistochemistry of HPV-16⁺ SCCHN tumors showed that these antigen-processing machinery components are down-regulated in tumors in vivo compared with adjacent normal squamous epithelium. Thus, immunity to HPV-16 E7 is associated with the presence of HPV-16 infection and presentation of E7-derived peptides on SCCHN cells, which show evidence of immune escape. These findings support further development of E7-specific immunotherapy and strategies for up-regulation of antigen-processing machinery components in HPV-associated SCCHN.

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