Combination of intratumoral injections of vaccinia virus MVA expressing GM-CSF and immunization with DNA vaccine prolongs the survival of mice bearing HPV16 induced tumors with downregulated expression of MHC class I molecules.
Downregulation of MHC class I molecules is believed to be often the cause of tumor immune escape and at the same time it is the major obstacle to T-cell based immunotherapy of tumors. In our experimental model, the C57BL/6 mice bearing tumors induced by TC-1/A9 cells characterized by expression of HPV16 oncogenes and downregulation of H-2b molecules were immunized with highly immunogenic E7GGG.GUS DNA vaccine expressing the fused gene of modified HPV16 E7 (E7GGG) with E.coli beta-glucuronidase (GUS). The DNA vaccine was administered by gene gun on days 7 and 14 after s.c. injection of tumor cells. The tumors in situ were injected with recombinant vaccinia virus MVA expressing the gene for murine granulocyte-macrophage colony-stimulating factor (MVA-GM-CSF). Two doses of the DNA vaccine combined with at least two consecutive local treatments with MVA-GM-CSF were able to inhibit significantly the growth of tumors. We have shown by ELISPOT-IFNgamma that in situ expression of the GM-CSF gene did not enhance the E7 specific systemic Tcell response. We found that local injections of MVA-GM-CSF induced an increase of intratumoral CD3+ T cell counts and that the DNA vaccination resulted in up-regulation of MHC type I molecules on tumor cells in vivo. We suppose that i.t. delivery of MVA-GM-CSF changed the local tumor microenvironment and rendered tumors more attractive and better accessible to effector T cells.
Nemeckova
S
S
Institute of Hematology and Blood Transfusion, Prague, Czech Republic. sarkan@uhkt.cz
Smahel
M
M
Hainz
P
P
Mackova
J
J
Zurkova
K
K
Gabriel
P
P
Indrova
M
M
Kutinova
L
L
D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage; D015536:Down-Regulation; D004926:Escherichia coli / Q000201:enzymology; D005260:Female; D015316:Genetic Therapy; D005966:Glucuronidase; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D006183:H-2 Antigens / Q000378:metabolism*; D052162:Human papillomavirus 16 / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018365:Neoplasm, Residual / Q000209:etiology / Q000473:pathology / Q000628:therapy; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000401:mortality*; D015996:Survival Rate; D014611:Vaccination; D019444:Vaccines, DNA / Q000008:administration & dosage*; D014616:Vaccinia virus / Q000235:genetics*