Cytotoxicity of human endogenous retrovirus K-specific T cells toward autologous ovarian cancer cells

• Published in: Clinical cancer research 2015-01, Vol.21 (2), p.471-483
• Main Authors: Rycaj, Kiera, Plummer, Joshua B, Yin, Bingnan, Li, Ming, Garza, Jeremy, Radvanyi, Laszlo, Ramondetta, Lois M, Lin, Kevin, Johanning, Gary L, Tang, Dean G, Wang-Johanning, Feng
• Format: Article
• Language: English
• Subjects: Antigens, Neoplasm - blood; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Cell Line, Tumor; Cell Proliferation; Cytotoxicity, Immunologic; Endogenous Retroviruses - genetics; Endogenous Retroviruses - metabolism; Female; Gene Products, env - blood; Gene Products, env - genetics; Humans; Lymphocyte Activation; Ovarian Neoplasms - blood; Ovarian Neoplasms - virology; RNA-Directed DNA Polymerase - blood; RNA-Directed DNA Polymerase - genetics; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - virology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-14-0388

To determine whether HERV-K envelope (ENV) protein could function as a tumor-associated antigen and elicit specific T-cell responses against autologous ovarian cancer cells. The expression of HERV-K transcripts and ENV protein, the presence of serum antibodies against HERV-K, reverse transcriptase (RT) activities, and cellular immune responses in primary ovarian cancer tissues and patient blood samples were analyzed and compared with samples from patients with benign ovarian diseases and normal female donors. Ovarian cancer cells in primary tumors and ascites expressed markers of cancer stem cells and markers of both mesenchymal and epithelial cells. Expression of HERV transcripts and HERV-K ENV protein and reverse transcriptase activities were higher in ovarian cancer compared with adjacent normal and benign tissues. The ovarian cancer patient plasma also had high reverse transcriptase activities and the ovarian cancer patient sera contained HERV-K immunoreactive antibodies. HERV-K-specific T cells generated from autologous dendritic cells pulsed with HERV-K ENV antigens exhibited phenotypes and functions consistent with a cellular immune response including T-cell proliferation, IFNγ production, and HERV-K-specific cytotoxic T lymphocyte (CTL) activity. Significantly higher CTL lysis of autologous tumor cells than of uninvolved normal cells was demonstrated in patients with ovarian cancer than patients with benign diseases and further enhanced lysis was observed if T regulatory cells were depleted. Endogenous retroviral gene products in ovarian cancer may represent a potentially valuable new pool of tumor-associated antigens for targeting of therapeutic vaccines to ovarian cancer. Clin Cancer Res; 21(2); 471-83. ©2014 AACR.