Immunization with Murine Breast Cancer Cells Treated with Antisense Oligodeoxynucleotides to Type I Insulin-like Growth Factor Receptor Induced an Antitumoral Effect Mediated by a CD8+-Response Involving Fas/Fas Ligand Cytotoxic Pathway.

SCHILLACI R; SALATINO M; CASSATARO J; PROIETTI CJ; GIAMBARTOLOMEI GH; RIVAS M; CARNEVALE R; CHARREAU EH; ELIZALDE PV

JOURNAL OF IMMUNOLOGY

American Association of Immunologists

Año: 2006 vol. 176 p. 3426 - 3437

0022-1767

We have demonstrated that in vivo administration of phosphorothioate antisense oligodeoxynucleotides (AS[S]ODN) to type I insulin-like growth factor receptor (IGF-IR) mRNA resulted in inhibition of C4HD breast cancer growth in Balb/c mice. The present study focused on whether in vivo administration of C4HD tumor cells pre-treated with IGF-IR AS[S]ODN and irradiated, could provide protection against C4HD wild-type tumor challenge, and to elucidate the mechanism mediating this effect. Our results showed that mice immunized with IGF-IR AS[S]ODN-treated C4HD cells, experienced a growth inhibition of 53.4%,  61.6% and  60.2% when compared to  PBS-treated mice, wild-type C4HD cells injected mice or Sense[S]ODN-treated C4HD cells injected mice respectively. The protective effect was C4HD-specific, since no cross-protection was observed against other syngeneic mammary tumor lines. The lack of protection against tumor formation in nude mice indicated that T cells were involved in the antitumoral response. Furthermore, cytotoxicity and splenocyte proliferation assays demonstrated that a cellular CD8+-dependent immune response acting through Fas/FasL death pathway, could be responsible for the antitumor effect induced by immunization with AS[S]ODN-treated cells. Immunization also induced splenocytes to produce Ag-dependent IFN-γ, indicating the presence of a type 1 response. Induction of the immunogenic phenotype in C4HD cells after treatment with AS[S]ODN, occurred along with induction of the expression of the peptide-chaperone protein Hsp70 and of the costimulatory molecule CD86. Our results have for the first time demonstrated that breast cancer growth can be inhibited in vivo through induction of a specific immune response with tumor immunogens derived from IGF-IR AS[S]ODN-treated breast tumor cells.