Dr. Feng Wang-Johanning
The University of Texas MD Anderson Cancer Center
Michale E. Keeling Center
Department of Veterinary Sciences
Department of Immunology
My laboratory is located in Bastrop, Texas, at UT Science Park – Veterinary Sciences.
- Human endogenous retroviruses
- Early detection, diagnosis and immunotherapy of solid tumors including breast, ovarian and other cancers
- Cancer vaccines
- Antibody therapy
HERV-K is a novel tumor-associated antigen for breast cancer: We were the first to systematically and convincingly document the specific role of HERV-K in breast cancer (BC) (Clinical Cancer Research, 2001)1. We reported that HERV-K is expressed at the transcriptional level in human BC tissues but not in normal or uninvolved human breast tissues. This idea was further advanced in our Oncogene publication in 20032, where our group reported the presence of novel splice donor and acceptor sites in BCs, which explains, in part, why HERV-K-encoding loci are transcriptionally silent in normal cells, and become active following malignant transformation. Anti-HERV-K antibodies have been detected in cancer patient sera, and the level of Ab titer correlated with treatment and recurrence of tumors. We found HERV-K env protein expression in 88% of BC (n = 119), but not in normal breast tissues (n = 76) (Cancer Research, 2008)3. Increased env expression of HERV-K in breast tumors (195 from US and 110 from China) was significantly associated with lymph node metastasis (accepted by JNCI, 2011). Although our published data suggest that HERV-K expression may correlate with disease progression in BC, almost nothing is known about the functional role of HERV-K proteins in tumor biology.
HERV-K antigens as BC vaccines: In our 2008 Cancer Research paper 3, we discovered that the HERV-K antigen clearly stimulated cellular immune responses by dendritic cell vaccines in BC patients. A T-cell response against HERV-K was detected in peripheral blood mononuclear cells (PBMC) from BC patients, but not in matched normal female controls. The patient responses included induction of T-cell proliferation, IFN-γ production measured by enzyme-linked immunospot (ELISPOT) and multiplex cytokine secretion, including significantly increased secretion of interleukin (IL)-2, IL-6, IL-8, and IP-10. HERV-K-specific cytotoxic T lymphocyte activity was observed against BC cells only in BC patients, but not in normal donors, and HERV-K antigens and peptides will be developed for clinical trials in the future.
HERV-K antibody therapy: Few immunotherapy approaches have been used for the treatment and prevention of cancer, despite the fact that researchers have been searching for years for ideal tumor-specific markers to help antibodies deliver drugs selectively to cancer cells and not to normal cells and tissues. We recently developed anti-HERV-K mAbs that demonstrated for the first time that env, or any protein encoded by an endogenous retrovirus, can be successfully targeted by a mAb therapy, leading to antitumor effects of anti-HERV-K env antibodies in vitro and in vivo (accepted by JNCI, 2011). Furthermore, the monoclonal antibodies we developed were able to deliver toxin to, and show florescence specifically in, BC cells and not normal cells. The mAbs were also capable of blocking BC cell proliferation and inducing apoptosis in BC cells. In addition, tumor sizes in xenograft mouse models implanted with human BC cells expressing HERV-K were highly significantly reduced after treatment with anti-HERV-K mAbs, and onset of tumorigenesis was significantly delayed in vivo. Gene expression and Western blot analyses revealed caspase activation and up-regulation of p53 pathway genes in env-positive BC cells after mAb exposure. Our findings show that anti-HERV-K mAbs may be a novel candidate therapeutic agent for BC therapy. This finding should have significant clinical implications because mAb therapy is already successfully used in clinical practice, and targeting HERV-K in BC may lead to disease regression when alternative therapies have failed.
Identify novel infectious retroviruses in BC patients: Of all human endogenous retroviruses known today, HERV-K is the only one that has been shown to produce viral particles 4, 5. HERV-K displays significant sequence similarities with mouse mammary tumor virus (MMTV), which is an infectious virus that plays an etiologic role in murine mammary tumors. It is unclear whether these germline viral sequences encode an infectious virus, but hormonal stimuli and stress factors can induce transcription of retroviral proteins and viable viral particles from several genomic loci that can be detected as cellular antigens and/or viral particles in tumor tissue and blood samples 6-8. HERV-K viral-like particles can be observed in teratocarcinoma 9, 10, melanoma-derived cell lines 11, the hormone stimulated T47D cell line 12, 13, and lymphoma patients 7. However, no functional provirus able to produce infectious particles has yet been described 14. Infectious particles were identified in an infectious progenitor (“resuscitating” Phoenix) using in vitro recombination of the multiple-copy HERV-K loci, which indicates that human cells still have the potential to produce infectious retroviruses 14-16. Our latest finding is that HERV-K viral particles appear to be infectious in some BC patients.
A tutorial in my laboratory will provide experience in molecular biology, virology and immunology related to cancer and viruses, and research techniques in: isolation of RNA and DNA, cDNA synthesis, laser microdissection, RT-PCR, real-time RT-PCR, cloning and sequencing, RNA in situ hybridization, protein expression and purification, ELISA, TEM, immunofluorescence, Biacore, flow cytometry, antibody production and purification, conjugation, immunohistochemistry, immunoprecipitation, gene transfection, Western blotting, Northern blot, microarray, tissue microarray, immunization of animals, animal models, imaging, transgenic mice, CTL assay, ELISPOT assay, isolation of CD8+ T cells, flow cytometry analysis of IFN-gamma, viral vector design and expression.
Wang-Johanning F, Rycaj K, Plummer J, Li M, Yin B, Frerich K, Garza J, Shen J, Lin K, Yan P, Glynn S, Dorsey T, Hunt K, Ambs S, Johanning G. Immunotherapeutic Potential of Anti-Human Endogenous Retrovirus-K Envelope Protein Antibodies in Targeting Breast Tumors. Journal of the National Cancer Institute 104(3):189-210, 1/2012.
Wang-Johanning F, Radvanyi L, Rycaj K, Plummer JB, Yan P, Sastry KJ, Piyathilake CJ, Hunt KK, Johanning GL. Human endogenous retrovirus K triggers an antigen-specific immune response in breast cancer patients. Cancer Res 68(14):5869-5877, 07/15/2008, 7/2008.
Wang-Johanning F, Frost AR, Jian B, Epp L, Lu DW, Johanning GL. Quantitation of HERV-K env gene expression and splicing in human breast cancer. Oncogene 22(10):1528-35, 3/2003.
Wang-Johanning F, Frost AR, Johanning GL, Khazaeli MB, LoBuglio AF, Shaw DR, Strong TV. Expression of human endogenous retrovirus k envelope transcripts in human breast cancer. Clin Cancer Res 7(6):1553-60, 6/2001.
Wang-Johanning F, Liu J, Rycaj K, Huang M, Tsai K, Rosen DG, Chen DT, Lu DW, Barnhart KF, Johanning GL. Expression of multiple human endogenous retrovirus envelope surface proteins in ovarian cancer. Int J Cancer 120(1):81-90, 1/2007.
Wang-Johanning F, Gillespie GY, Grim J, Rancourt C, Alvarez RD, Siegal GP, Curiel DT. Intracellular expression of a single-chain antibody directed against human papillomavirus type 16 E7 oncoprotein achieves targeted antineoplastic effects. Cancer Res 58(9):1893-1900, 5/1998.