alpha-Tocopheryloxyacetic acid: a novel chemotherapeutic that stimulates the antitumor immune response

Abstract

INTRODUCTION:alpha-Tocopheryloxyacetic acid (alpha-TEA) is a novel ether derivative of alpha-tocopherol that has generated interest as a chemotherapeutic agent because of its selective toxicity toward tumor cells and its ability to suppress tumor growth in various rodent and human xenograft models. We previously reported that oral alpha-TEA inhibited the growth of both a transplanted (4T1) and a spontaneous MMTV-PyMT mouse model of breast cancer.METHODS:Because little is known about the possible immunological mechanisms underlying the in vivo alpha-TEA effects, we evaluated the impact of alpha-TEA therapy on the immune response by characterizing immune cell populations infiltrating the tumor site.RESULTS:alpha-TEA treatment resulted in higher frequencies of activated T cells in the tumor microenvironment and twofold and sixfold higher ratios of CD4+ and CD8+ T cells to regulatory T cells, respectively. This finding was correlated with an increased ability of tumor-draining lymph node cells and splenocytes from alpha-TEA-treated mice to secrete interferon (IFN)-gamma in response to CD3 or to mediate a cytolytic response in a tumor-specific fashion, respectively. That the alpha-TEA-mediated antitumor effect had a T cell-dependent component was demonstrated by the partial abrogation of tumor suppression when CD4+ and CD8+ T cells were depleted. We also determined the intratumoral cytokine and chemokine profile and found that alpha-TEA treatment increased intratumoral IFN-gamma levels but decreased interleukin (IL)-4 levels, suggesting a shift toward a TH1 response. In addition, alpha-TEA induced higher levels of the inflammatory cytokine IL-6 and the chemokine CCL5.CONCLUSIONS:Taken together, these data suggest that alpha-TEA treatment, in addition to its direct cytotoxic effects, enhanced the anti-tumor immune response. This study provides a better understanding of the mechanisms of action of alpha-TEA and its effect on the immune system and may prove useful in designing immune-stimulating strategies to boost the antitumor effects of alpha-TEA in breast cancer patients.