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Peripheral tolerance to human papillomavirus E7 oncoprotein occurs by cross-tolerization, is largely
T Doan1, K A Herd, P F Lambert
1Sir Albert Sakzewski Virus Research Centre, University of Queensland, Royal Children's Hospital, Herston, Australia.
Abstract:
The E7 oncoprotein of human papillomavirus 16 functions as a tumor-specific antigen in transformed epithelial cells of the uterine cervix to which immunotherapeutic strategies aimed at CTL induction may be directed. We previously have shown in mice transgenic for the E7 gene driven off an epithelial specific (keratin-14) promoter, that expression of E7 protein in peripheral epithelium is sufficient to tolerize E7-directed CTL precursors (pCTL; Doan et al, J. Virol., 73: 6166-1670, 1999). Here we show that E7 is presented to T cells for tolerization by cells of bone marrow origin ("cross-tolerization"). We demonstrate that tolerization of E7-directed pCTLs occurs within 2 weeks of exposure to E7 in epithelium. It is maintained in the near absence of CD4+ cells and in the absence of the thymus, and is independent of a coexisting E7-directed Th2-type antibody response. Tolerance was broken by immunization with E7 CTL epitope-pulsed dendritic cells. These findings have implications for immunotherapy of patients with human papillomavirus 16-associated cervical carcinoma, whose immune systems may have experienced long-term exposure to E7-expressing epithelial cells.
Insights
Human papillomavirus 16 E7 protein causes immune tolerance in mice, preventing anti-tumor T cell responses. This tolerance can be broken by dendritic cell immunization, offering hope for cervical cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Human papillomavirus 16 (HPV16) E7 oncoprotein is a tumor antigen in cervical cancer.
- E7 expression in epithelial cells can induce immune tolerance, hindering anti-tumor responses.
Purpose of the Study:
- To investigate the mechanism of E7-induced immune tolerance.
- To determine if tolerance can be overcome for therapeutic benefit.
Main Methods:
- Mice transgenic for the E7 gene were used to study immune tolerance.
- Tolerization of E7-directed cytotoxic T lymphocyte (CTL) precursors was assessed.
- Tolerance was broken using E7 CTL epitope-pulsed dendritic cells.
Main Results:
- E7-induced immune tolerance is mediated by bone marrow-derived cells through cross-tolerization.
- Tolerance develops rapidly (within 2 weeks) and is maintained independently of CD4+ T cells, thymus, or Th2 antibody responses.
- Immunization with E7 epitope-pulsed dendritic cells successfully broke established tolerance.
Conclusions:
- HPV16 E7 induces a robust immune tolerance mechanism involving cross-presentation by bone marrow cells.
- Breaking this tolerance via dendritic cell therapy is a potential strategy for HPV16-associated cervical cancer immunotherapy.