title: CD8+ T cells, NK cells and IFN-gamma are important for control of tumor with downregulated MHC class I expression by DNA vaccination.
abstract: One of the major hurdles facing cancer immunotherapy is that cancers may downregulate expression of MHC class I molecules. The development of a suitable tumor model with downregulated MHC class I expression is critical for designing vaccines and immunotherapeutic strategies to control such tumors. We developed an E7-expressing murine tumor model with downregulated MHC class I expression, TC-1 P3 (A15). Using this model, we tested DNA and vaccinia vaccines for their ability to control tumors with downregulated MHC class I expression. We found that vaccination with DNA encoding E7 linked to Mycobacterial heat shock protein 70 (HSP70) generated a significant antitumor effect against TC-1 P3 (A15), while vaccination with E7/HSP70 vaccinia did not generate an appreciable antitumor effect. Lymphocyte depletion experiments revealed that both CD8+ T cells and NK cells were essential for the antitumor effect generated by E7/HSP70 DNA against TC-1 P3 (A15). Furthermore, tumor protection experiments using IFN-gamma knockout mice revealed that IFN-gamma was essential for the antitumor effect generated by E7/HSP70 DNA against TC-1 P3 (A15). Our results demonstrate that vaccination with E7/HSP70 DNA results in a significant antitumor effect against a neoplasm with downregulated MHC class I expression and the importance of CD8+ T cells, NK cells, and IFN-gamma in generating this antitumor effect.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: W F
authors.initials: WF
authors.lastname: Cheng
authors.forename: C F
authors.initials: CF
authors.lastname: Hung
authors.forename: K Y
authors.initials: KY
authors.lastname: Lin
authors.forename: M
authors.initials: M
authors.lastname: Ling
authors.forename: J
authors.initials: J
authors.lastname: Juang
authors.forename: L
authors.initials: L
authors.lastname: He
authors.forename: C T
authors.initials: CT
authors.lastname: Lin
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000032:analysis; D005260:Female; D005434:Flow Cytometry; D005805:Genes, MHC Class I; D015316:Genetic Therapy / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D019444:Vaccines, DNA / Q000008:administration & dosage*
chemical_list: D016207:Cytokines; D019444:Vaccines, DNA; D007371:Interferon-gamma