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EnglishIn the Balb/c genetic background, the MHC-I H-2 Ld molecule is the restriction element presenting the immunodominant epitopes of the two most common mouse tumor associated antigens P1A and gp70: The Balb/c derived Sp6 mouse plasmacytoma show a downregulated cell surface expression of H-2 Ld, still maintaining normal expression levels of H-2 Kd and Dd. On the contrary, both P1A and gp70 are expressed at the transcription level, but Sp6 appeared able to present to specific T cell lines the endogenous gp70-AH1 (gp70423-431) immunodominant epitope only. Sp6 cells were transduced with B7-1 and Ld specific cDNAs. De novo expression of B7-1 costimulatory molecule rendered Sp6 tumor immunogenic: animals injected subcutaneously, intraperitoneally, intravenously or intraspleen with Sp6/B7 either did not show tumor growth or they developed tumors regressing in few days. Nevertheless only the subcutaneous route of immunization with Sp6/B7-Sp6/B7/Ld induced a protective response against wild type tumor cells. Accordingly, Sp6 and Sp6/Ld-specific cytotoxic activity was detected only in the spleen and draining lymph nodes of subcutaneously injected animals. In vivo depletion of the CD8+ and/or CD4+ T cell populations indicated that the T CD8+ cells are the effectors responsible for elimination of B7-1 positive tumor cells, although the T CD4+ cells are required for the induction of a memory CTL response, able to eliminate B7-1 negative Sp6 tumors. Restoration of Ld expression to normal levels in the Sp6 tumorigenic form (Sp6/Ld) lowered the antigenic dose required to induce a systemic protection, independently of which immunogenic form of Sp6 (Sp6/B7 or Sp6/B7/Ld) was employed for immunization, but it was protective against the Ld-expressing form of Sp6 tumor only. On the contrary, the response elicited by immunization with Sp6/B7, although requiring higher antigen doses than immunization with Sp6/B7Ld, was able to induce systemic protection against both the Ld-positive and the Ld-negative tumor forms. Finally, although Sp6 cells resulted able to present their own endogenous gp70 immunodominant epitope to specific T cell lines, the immune response elicited by in vivo immunization with the autologous, B7-1 positive cellular vaccine, either Sp6/B7 or Sp6/B7/Ld, never resulted gp70-specific. Therefore we analyzed ex vivo gp70 expression in B7-1 positive and negative tumors explanted from mice subcutaneously injected and before tumor regression, both freshly explanted or after two weeks of in vitro culture. RT-PCR analysis showed loss of gp70 expression in B7-1 positive tumors. This expression was reconstituted following two weeks of in vitro culture. On the contrary, B7-1 negative tumors always showed gp70 expression. These results suggest a scenario where Sp6 tumor carried out two immunoescape mechanisms: i) downregulation of immunodominant antigens, turned on when interacting with the immune system in the immunogenic, B7-1 expressing form; ii) Ld downregulation, allowing to escape eventual gp70-specific immune response elicited by professional APCs endocyting gp-70-containing tumor cell debris. Downregulation of gp70 in Sp6/B7-immunizing cells probably shaped the immune response against different tumor antigens, still Ld restricted, as indicated by the fact that the immune response elicited by Sp6/B7 is more effective against Sp6/Ld than Sp6 at low vaccine doses. In conclusion, despite the identification of tumor antigens and their use as cancer vaccines, autologous tumor cell vaccines still remain a potent tool for generating anti-tumor immunity, expecially when tumors adopt immunoescape mechanisms such as downregulation-loss of MHC haplotypes as well of immunodominant antigenic epitopes. In addition, several factors like antigen dose, site of delivery and time schedule of immunization can influence vaccine efficiency.
| Titolo: | Autologous cellular vaccine allows control of cancer immunoediting in a mouse model of plasmacytoma. | |
| Autori: | ||
| Data di pubblicazione: | 2005 | |
| Abstract: | In the Balb/c genetic background, the MHC-I H-2 Ld molecule is the restriction element presenting the immunodominant epitopes of the two most common mouse tumor associated antigens P1A and gp70: The Balb/c derived Sp6 mouse plasmacytoma show a downregulated cell surface expression of H-2 Ld, still maintaining normal expression levels of H-2 Kd and Dd. On the contrary, both P1A and gp70 are expressed at the transcription level, but Sp6 appeared able to present to specific T cell lines the endogenous gp70-AH1 (gp70423-431) immunodominant epitope only. Sp6 cells were transduced with B7-1 and Ld specific cDNAs. De novo expression of B7-1 costimulatory molecule rendered Sp6 tumor immunogenic: animals injected subcutaneously, intraperitoneally, intravenously or intraspleen with Sp6/B7 either did not show tumor growth or they developed tumors regressing in few days. Nevertheless only the subcutaneous route of immunization with Sp6/B7-Sp6/B7/Ld induced a protective response against wild type tumor cells. Accordingly, Sp6 and Sp6/Ld-specific cytotoxic activity was detected only in the spleen and draining lymph nodes of subcutaneously injected animals. In vivo depletion of the CD8+ and/or CD4+ T cell populations indicated that the T CD8+ cells are the effectors responsible for elimination of B7-1 positive tumor cells, although the T CD4+ cells are required for the induction of a memory CTL response, able to eliminate B7-1 negative Sp6 tumors. Restoration of Ld expression to normal levels in the Sp6 tumorigenic form (Sp6/Ld) lowered the antigenic dose required to induce a systemic protection, independently of which immunogenic form of Sp6 (Sp6/B7 or Sp6/B7/Ld) was employed for immunization, but it was protective against the Ld-expressing form of Sp6 tumor only. On the contrary, the response elicited by immunization with Sp6/B7, although requiring higher antigen doses than immunization with Sp6/B7Ld, was able to induce systemic protection against both the Ld-positive and the Ld-negative tumor forms. Finally, although Sp6 cells resulted able to present their own endogenous gp70 immunodominant epitope to specific T cell lines, the immune response elicited by in vivo immunization with the autologous, B7-1 positive cellular vaccine, either Sp6/B7 or Sp6/B7/Ld, never resulted gp70-specific. Therefore we analyzed ex vivo gp70 expression in B7-1 positive and negative tumors explanted from mice subcutaneously injected and before tumor regression, both freshly explanted or after two weeks of in vitro culture. RT-PCR analysis showed loss of gp70 expression in B7-1 positive tumors. This expression was reconstituted following two weeks of in vitro culture. On the contrary, B7-1 negative tumors always showed gp70 expression. These results suggest a scenario where Sp6 tumor carried out two immunoescape mechanisms: i) downregulation of immunodominant antigens, turned on when interacting with the immune system in the immunogenic, B7-1 expressing form; ii) Ld downregulation, allowing to escape eventual gp70-specific immune response elicited by professional APCs endocyting gp-70-containing tumor cell debris. Downregulation of gp70 in Sp6/B7-immunizing cells probably shaped the immune response against different tumor antigens, still Ld restricted, as indicated by the fact that the immune response elicited by Sp6/B7 is more effective against Sp6/Ld than Sp6 at low vaccine doses. In conclusion, despite the identification of tumor antigens and their use as cancer vaccines, autologous tumor cell vaccines still remain a potent tool for generating anti-tumor immunity, expecially when tumors adopt immunoescape mechanisms such as downregulation-loss of MHC haplotypes as well of immunodominant antigenic epitopes. In addition, several factors like antigen dose, site of delivery and time schedule of immunization can influence vaccine efficiency. | |
| Handle: | http://hdl.handle.net/11562/27333 | |
| Appare nelle tipologie: | 04.01 Contributo in atti di convegno |
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