Main obstacles to cancer vaccine efficacy are pre-existing antigenic load and immunoescape mechanisms, including tolerance against self tumor-associated antigens. Here we explored the role of tolerance in an antimetastatic vaccine approach based on dendritic cell-tumor cell (DC-TC) hybrids, thanks to the comparison between BALB-neuT mice, transgenic for and tolerant to rat HER-2/neu, with their non-tolerant strain of origin BALB/c. Allogeneic DC-TC hybrid vaccine displayed a high antimetastatic activity in non-tolerant mice, but was far less effective in tolerant mice, even with intensified vaccine schedule. Tolerant BALB-neuT mice revealed a reduced ability to mount polarized Th1 responses. A further attempt to increase the antimetastatic activity by using LPS-matured DC hybrids failed. Allogeneic LPS-matured DC-TC hybrids induced high IFN-γ levels, but concomitantly also the highest production of IL-4 and IL-10 suggesting activation of mechanisms sustaining regulatory cells able to blunt vaccine efficacy. Our data in tolerant versus non-tolerant hosts suggest that clinical translation of effective DC-based strategies could benefit from more extensive investigations in tolerant transgenic models.

HER-2/neu tolerant and non-tolerant mice for fine assessment of antimetastatic potency of dendritic cell-tumor cell hybrid vaccines

LANDUZZI, LORENA;ANTOGNOLI, AGNESE;CROCI, STEFANIA;PALLADINI, ARIANNA;IANZANO, MARIANNA LUCIA;MURGO, ANNALISA;STIVANI, VALERIA;GROSSO, VALENTINA;NANNI, PATRIZIA;DE GIOVANNI, CARLA;LOLLINI, PIER LUIGI
2011

Abstract

Main obstacles to cancer vaccine efficacy are pre-existing antigenic load and immunoescape mechanisms, including tolerance against self tumor-associated antigens. Here we explored the role of tolerance in an antimetastatic vaccine approach based on dendritic cell-tumor cell (DC-TC) hybrids, thanks to the comparison between BALB-neuT mice, transgenic for and tolerant to rat HER-2/neu, with their non-tolerant strain of origin BALB/c. Allogeneic DC-TC hybrid vaccine displayed a high antimetastatic activity in non-tolerant mice, but was far less effective in tolerant mice, even with intensified vaccine schedule. Tolerant BALB-neuT mice revealed a reduced ability to mount polarized Th1 responses. A further attempt to increase the antimetastatic activity by using LPS-matured DC hybrids failed. Allogeneic LPS-matured DC-TC hybrids induced high IFN-γ levels, but concomitantly also the highest production of IL-4 and IL-10 suggesting activation of mechanisms sustaining regulatory cells able to blunt vaccine efficacy. Our data in tolerant versus non-tolerant hosts suggest that clinical translation of effective DC-based strategies could benefit from more extensive investigations in tolerant transgenic models.
L.Landuzzi; A. Antognoli; G. Nicoletti; S. Croci; A. Palladini; ML. Ianzano; A. Murgo; V. Stivani; V. Grosso; P. Nanni; C. De Giovanni; P. Lollini
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/112236
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