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In the FVB/N HER-2/neu transgenic mouse both peripheral and central tolerance limit the immune response targeting HER-2/neu induced by Listeria monocytogenes-based vaccines

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Abstract

Listeria monocytogenes-based vaccines for HER-2/neu are capable of breaking tolerance in FVB/N rat HER-2/neu transgenic mice. The growth of implanted NT-2 tumors, derived from a spontaneously occurring tumor in the FVB/N HER-2/neu transgenic mouse, was significantly slower in these mice following vaccination with a series of L. monocytogenes-based vaccines for HER-2/neu. Mechanisms of T cell tolerance that exist in these transgenic mice include the absence of functional high avidity anti-HER-2/neu CD8+ T cells and the presence of CD4+CD25+ regulatory T cells. The in vivo depletion of these regulatory T cells resulted in the slowing in growth of tumors even without the treatment of mice with an anti-HER-2/neu vaccine. The average avidities of responsive CD8+ T cells to six of the nine epitopes in HER-2/neu we examined, four of which were identified in this study, are shown here to be of a lower average avidity in the transgenic mice versus wild type FVB/N mice. In contrast, the average avidity of CD8+ T cells to three epitopes that showed the lowest avidity in the wild-type mice did not differ between wild type and transgenic mice. This study demonstrates the ability of L. monocytogenes-based vaccines to impact upon tolerance to HER-2/neu in FVB/N HER-2/neu transgenic mice and further defines some of the aspects of tolerance in these mice.

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Acknowledgments

We would like to thank Dr. Mark Greene (University of Pennsylvania, Philadelphia, PA) for the generous donation of the 7.21.2 hybridoma cell line and Dr. Gail Massey (University of Pennsylvania, Philadelphia, PA) for her assistance in culturing this cell line. We would also like to thank. Dr. Paulo Maciag (University of Pennsylvania, Philadelphia, PA) for allowing us to use Lm-LLO-NY-ESO-1 prior to publication and Dr. Zhen-Kun Pan (University of Pennsylvania, Philadelphia, PA) for her assistance with the mouse work. Yvonne Paterson wishes to disclose that she has a financial interest in Advaxis, Inc., a vaccine and therapeutic company that has licensed or has an option to license all patents from the University of Pennsylvania that concern the use of Listeria or listerial products as vaccines.

This work was supported by Department of Defense Grant W81XWH-04-1-0338 (R.S.) and NIH R01CA109253 (Y.P.).

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  1. Department of Microbiology, School of Medicine, University of Pennsylvania, 323 Johnson Pavilion, 36th St. and Hamilton Walk, Philadelphia, PA, 19104-6076, USA

    Reshma Singh & Yvonne Paterson

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  1. Reshma Singh
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Correspondence to Yvonne Paterson.

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Singh, R., Paterson, Y. In the FVB/N HER-2/neu transgenic mouse both peripheral and central tolerance limit the immune response targeting HER-2/neu induced by Listeria monocytogenes-based vaccines. Cancer Immunol Immunother 56, 927–938 (2007). https://doi.org/10.1007/s00262-006-0237-4

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