© 2004 by Oxford University Press
© 2004 Oxford University Press
ARTICLE |
Impaired Antigen Presentation and Effectiveness of Combined Active/Passive Immunotherapy for Epithelial Tumors
Affiliations of authors: Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia (KM, GRL, JZ, XL, RLDK, TP, GJPF, IHF); McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine, Madison, WI (AL, PFL)
Correspondence to: I. H. Frazer, MbChB, MD, FAA, Centre for Immunology and Cancer Research, The University of Queensland, Research Wing, Building 1, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia (e-mail: ifrazer{at}cicr.uq.edu.au)
Background: Although immunization with tumor antigens can eliminate many transplantable tumors in animal models, immune effector mechanisms associated with successful immunotherapy of epithelial cancers remain undefined. Methods: Skin from transgenic mice expressing the cervical cancer–associated tumor antigen human papillomavirus type 16 (HPV16) E6 or E7 proteins from a keratin 14 promoter was grafted onto syngeneic, non-transgenic mice. Skin graft rejection was measured after active immunization with HPV16 E7 and adoptive transfer of antigen-specific T cells. Cytokine secretion of lymphocytes from mice receiving skin grafts and immunotherapy was detected by enzyme-linked immunosorbent assay, and HPV16 E7–specific memory CD8+ T cells were detected by flow cytometry and ELISPOT. Results: Skin grafts containing HPV16 E6–or E7–expressing keratinocytes were not rejected spontaneously or following immunization with E7 protein and adjuvant. Adoptive transfer of E7-specific T-cell receptor transgenic CD8+ T cells combined with immunization resulted in induction of antigen-specific interferon gamma–secreting CD8+ T cells and rejection of HPV16 E7–expressing grafts. Specific memory CD8+ T cells were generated by immunotherapy. However, a further HPV16 E7 graft was rejected from animals with memory T cells only after a second E7 immunization. Conclusions: Antigen-specific CD8+ T cells can destroy epithelium expressing HPV16 E7 tumor antigen, but presentation of E7 antigen from skin is insufficient to reactivate memory CD8+ T cells induced by immunotherapy. Thus, effective cancer immunotherapy in humans may need to invoke sufficient effector as well as memory T cells.
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