Regulating the high avidity, tumor-reactive CD8+ T cell response in the setting of immune tolerance

The potential of treating cancer using a patient's own immune system has intrigued scientists for decades. However, a major barrier to successful antitumor vaccination is tolerance of high-avidity T cells specific to tumor antigens. I have used the MMTV-HER-2/neu (neu-N) transgenic mouse to study the effects of immune tolerance on high-avidity, HER-2/neu (neu)-specific CD8+ T cells during initial immune activation and subsequent effector function at the tumor site. HER-2/neu (neu)-targeted vaccines, which raise strong CD8+ T cell responses to a dominant peptide (RNEU420-429) in wild-type FVB/N mice and protect them from a neu-expressing tumor challenge, fail to do so in the neu-N mice. However, I have shown that high avidity RNEU420-429-specific T cells can be activated in neu-N mice following immune modulatory treatments that inhibit CD4+CD25+ regulatory T (T reg) cells. I also demonstrated that Cyclophosphamide pretreatment deletes the actively dividing population of CD4+CD25+ T reg cells, allowing subsequent vaccine to activate the high avidity RNEU 420-429-specific T cells in the neu-N mice. These findings show that neu-N mice possess latent pools of high-avidity neu-specific CD8+ T cells that can be recruited to produce an effective antitumor response if T reg cells are blocked or removed. My second emphasis of studying the ongoing immune response in the tumor microenvironment demonstrated that CD4+Foxp3+ T reg cells are present in the tumors undergoing immune attack. However, the presence of T regs does not correlate with outcome as they are found in progressing and regressing tumors. In addition, I characterized a novel anti-tumor "effector" CD8+Foxp3+ T cell population found exclusively in the tumors. These findings challenge and dispel current paradigms in the field of immune tolerance, opening new avenues of understanding into how the immune system can be employed to treat cancers.