Erbb2 DNA Vaccine Combined with Regulatory T Cell Deletion Enhances Antibody Response and Reveals Latent Low-Avidity T Cells: Potential and Limits of Its Therapeutic Efficacy

Abstract

Rat (r)Erbb2 transgenic BALB-neuT mice genetically predestined to develop multiple invasive carcinomas allow an assessment of the potential of a vaccine against the stages of cancer progression. Because of rErbb2 expression in the thymus and its overexpression in the mammary gland, CD8+ T cell clones reacting at high avidity with dominant rErbb2 epitopes are deleted in these mice. In BALB-neuT mice with diffuse and invasive in situ lesions and almost palpable carcinomas, a temporary regulatory T cells depletion combined with anti-rErbb2 vaccine markedly enhanced the anti-rErbb2 Ab response and allowed the expansion of latent pools of low-avidity CD8+ T cells bearing TCRs repertoire reacting with the rErbb2 dominant peptide. This combination of a higher Ab response and activation of a low-avidity cytotoxic response persistently blocked tumor progression at stages in which the vaccine alone was ineffective. However, when diffuse and invasive microscopic cancers become almost palpable, this combination was no longer able to secure a significant extension of mice survival.

Antitumor immunization of mothers delays tumor development in cancer-prone offspring

“…21 On the other hand, in 71% of neu C ECTM offspring, there was expansion of low-avidity CD8 C T cells bearing the Vb6-Jb2.7 TCR rearrangement that is typical of ECTM-vaccinated BALBneuT, but not BALB/c, mice. 22 Indeed, we have recently shown how a temporary Treg depletion and ECTM vaccination in BALBneuT mice was able to induce the expansion of latent pools of lowavidity CD8 C T cells bearing TCR repertoires that react with p63-71. 22 The Vb6-Jb2.7 rearrangement, the same that expanded in neu C ECTM offspring in the present study, was among them.…”

“…22 Indeed, we have recently shown how a temporary Treg depletion and ECTM vaccination in BALBneuT mice was able to induce the expansion of latent pools of lowavidity CD8 C T cells bearing TCR repertoires that react with p63-71. 22 The Vb6-Jb2.7 rearrangement, the same that expanded in neu C ECTM offspring in the present study, was among them. Preliminary data show a decrease in spleen-derived Treg percentage in neu C ECTM offspring as compared to neu C control offspring at the fifth week of age (data not shown).…”

“…This is a low-avidity CD8 C T-cell clone that is specific for p63-71 and is induced by ECTM vaccination, but normally controlled by peripheral tolerance mechanisms such as T-regulatory cell (Treg) expansion in adult BALB-neuT mice. 22 The Vb6-Jb2.7 rearrangement expansion was found in 5 out of 7 neu C ECTM offspring and in none of the neu C control offspring (Fig. 5B).…”

“…19,20 Vaccine-elicited tumor inhibition in these mice is driven by anti-neu antibody generation, 16,17 whereas the T-cell cytotoxic response is marginal as T cells that react against neu with high affinity are wiped out by central tolerance. 21,22 The induction of high levels of antibodies following vaccination is also the mainstay of the success of maternal immunization strategy against infectious diseases. In the present study, we seek to evaluate whether maternal immunization can also induce an anti-neu immune response capable of hampering spontaneous tumor progression in BALB-neuT offspring.…”

In vivoModulation of Avidity in Highly Sensitive CD8+Effector T Cells Following Viral Infection

“…That said, there may be circumstances wherein lower avidity cells play a critical role. For example, cells exhibiting reduced avidity may be protected from exhaustion in models of chronic antigen exposure (15) and may play important roles in the clearance of some tumor cells (54,57,58).…”