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

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.

Immunoediting Sculpts Tumor Epitopes during Immunotherapy

“…We have described Listeria monocytogenes-based vaccines expressing overlapping fragments of HER-2/neu that are equally capable of inducing stasis in the growth of transplanted tumors in wild-type FVB/N mice (9) and HER-2/neu transgenic mice (10). We now show that these vaccines differ in delaying the onset of autochthonous tumor growth in transgenic mice.…”

“…The 3T3 cell line is a mouse fibroblast line that expresses MHC class I molecules of the ''q'' haplotype. The propagation of NT-2 and 3T3 cells has been previously described in detail (10)(11)(12) used in a standard CTL assay with 3T3 target cells loaded with 1 Ag/mL of the target peptide as described previously (10,12).…”

Harnessing Listeria monocytogenes to target tumors

“…Also, vaccination with Listeria vaccines expressing fragments of Her2/neu, fused to LLO, were effective against primary tumors in a syngeneic mouse breast tumor model, NT-2, expressing Her2/neu, which correlated with strong immune responses to Her2/neu. 54 These vaccines were also effective against NT-2 when implanted into a syngeneic HER-2/neu transgenic mouse, 55 which displays profound tolerance to HER-2/neu. Female HER-2/neu transgenic mice develop mammary tumors by about 5-9 mo of age but the HER-2/neu expressing Listeria vaccines delayed the appearance of mammary tumors in these mice.…”

Cancer immunotherapy using recombinantListeria monocytogenes: Transition from bench to clinic

“…60,[63][64][65] Using transgenic mouse models of cancer, L. monocytogenes based vaccines have been shown to have an ability to overcome tolerance mechanisms and mount an efficient immune response towards the tumors. 66,67 These studies have also shown that Listeria-based vaccines can impact on both central and peripheral tolerance mechanisms. In addition, it has been demonstrated that an immune response to overcome these tolerance mechanisms can have a therapeutic effect on the growth of both transplanted and spontaneous tumors in these models.…”

“…In addition, it has been demonstrated that an immune response to overcome these tolerance mechanisms can have a therapeutic effect on the growth of both transplanted and spontaneous tumors in these models. 66,67 The ability to overcome tolerance in these mouse models is an important aspect of these therapies as treatments that are effective in animals tolerant to the tumor antigen will theoretically have a greater chance of being effective in human clinical trials.…”