Effective genetic vaccination with a widely shared endogenous retroviral tumor antigen requires CD40 stimulation during tumor rejection phase.
Endogenous retrovirus (ERV) products are recognized by T lymphocytes in mice and humans. As these Ags are preferentially expressed by neoplastic tissues, they might represent an ideal target for active immunization by genetic vaccination. However, i.m. inoculation of plasmid DNA encoding mouse gp70 or p15E, two products of the env gene of an endogenous murine leukemia virus, elicited a weak Ag-specific T lymphocyte response and resulted in partial protection from challenge with mouse tumors possessing these Ags. Depletion experiments showed that CD8(+), but not CD4(+), T lymphocytes were crucial for the antitumor activity of the vaccines. Systemic administration of agonistic anti-CD40 mAb increased the therapeutic potential of genetic vaccination, but only when given during the tumor rejection phase and not at the time of immunization. This effect correlated with a dramatic increase in the number of ERV-specific CD8(+) T lymphocytes. Adjuvant activity of CD40 agonists thus seems to be relevant to enhance the CD8(+) T cell-dependent response in tumor-bearing hosts, suggesting that sustaining tumor-specific T lymphocyte survival in subjects undergoing vaccination might be a key event in the successful vaccination with weak tumor Ags.
Bronte
Vincenzo
V
Department of Oncology and Surgical Sciences, University of Padova, Padova, Italy. enzo.bronte@unipd.it
Cingarlini
Sara
S
Apolloni
Elisa
E
Serafini
Paolo
P
Marigo
Ilaria
I
De Santo
Carmela
C
Macino
Beatrice
B
Marin
Oriano
O
Zanovello
Paola
P
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D020077:Endogenous Retroviruses / Q000235:genetics* / Q000276:immunology*; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015682:Retroviridae Proteins, Oncogenic / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
D000957:Antigens, Viral, Tumor; D019013:CD40 Antigens; D016056:Immunodominant Epitopes; D015682:Retroviridae Proteins, Oncogenic; D019444:Vaccines, DNA; D014759:Viral Envelope Proteins; D014765:Viral Vaccines; C078678:p15E protein, Murine leukemia virus