Cytotoxicity of Human Endogenous Retrovirus K–Specific T Cells toward Autologous Ovarian Cancer Cells

Abstract

Purpose: 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.Experimental Design: 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.Results: 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, IFNg 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.Conclusion: Endogenous retroviral gene products in ovarian cancer may represent a potentially valuable new pool of tumorassociated antigens for targeting of therapeutic vaccines to ovarian cancer.

Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth

“…Viral-like particles with elevated RT activities were also found to be released from Panc-2 or Panc-1 cell lines, a finding similar to that reported by another group in lymphoma and breast cancer (22), suggesting the potential for activation of the HERV-K virus in PC. Other tumor types, such as primary and metastatic melanoma cell lines have also been found to express HERV-K viral RT (46,65), and HERV-K RT was increased in tumor tissues of breast cancer patients or ovarian cancer patients, correlating with poor prognosis and decreased overall survival (19,66). Furthermore, the higher titers of antibodies against the viral proteins HERV-K Env and NP9 observed in PC patients than in controls, and higher vRNA levels including HERV-K env and gag in the sera of PC patients than in the sera of normal donors suggests that an ongoing adaptive immune response is generated against HERV-K in PC patients.…”

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

“…These are ongoing for NSCLC (Brahmer, 2015) and planned for advanced ovarian cancer. Moreover, ERV-K env proteins have been shown to increase immunotherapeutic potential of melanoma, breast, and ovarian cancer patients (Rycaj et al, 2014;Wang-Johanning et al, 2012) (Cooper et al, 2015). Also, our hypotheses that drugs like Aza might sensitize patients with multiple cancer types to immune checkpoint blockade and other immunotherapies are further strengthened by the data in our pre-clinical melanoma model.…”

“…Some cancers lose ERV DNA methylation and aberrantly overexpress ERVs Cohen et al, 1988;Larsen et al, 2009;Larsson et al, 2007;Rycaj et al, 2014;Strick et al, 2007;Strissel et al, 2012;Wang-Johanning et al, 2001;Wang-Johanning et al, 2007) while others maintain silencing. Aza can induce specific ERV transcripts in melanoma, choriocarcinoma, and endometrial cancer cells (Laska et al, 2013;Ruebner et al, 2013;Stengel et al, 2010) (Strissel et al, 2012).…”

Resposta imune contra HERV-K em pacientes com câncer de próstata localizado e metastático

“…Neste estudo pode-se demonstrar aumento de transcrição gênica de HERV-K nas pacientes com câncer de ovário, bem como presença de anticorpos contra proteína de HERV-K-env e presença de linfócitos sensibilizado contra estas mesmas proteínas, por ensaio de ELISPOT-interferon gama. Demonstrou-se também que estes linfócitos sensibilizados mostraram atividade citolítica aumentada (62) .…”

“…Em nosso estudo não fizemos restrição de HLA. Dos poucos estudos que levantamos, nominalmente em tumores germinativo (61) , câncer de mama (56) , câncer de ovário (62) (84,85) . Algumas premissas importantes devem constar.…”