Abstract
Introductionα-Tocopheryloxyacetic acid (α-TEA) is a novel ether derivative of α-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 α-TEA inhibited the growth of both a transplanted (4T1) and a spontaneous MMTV-PyMT mouse model of breast cancer.MethodsBecause little is known about the possible immunological mechanisms underlying the in vivo α-TEA effects, we evaluated the impact of α-TEA therapy on the immune response by characterizing immune cell populations infiltrating the tumor site.Resultsα-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 α-TEA-treated mice to secrete interferon (IFN)-γ in response to CD3 or to mediate a cytolytic response in a tumor-specific fashion, respectively. That the α-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 α-TEA treatment increased intratumoral IFN-γ levels but decreased interleukin (IL)-4 levels, suggesting a shift toward a TH1 response. In addition, α-TEA induced higher levels of the inflammatory cytokine IL-6 and the chemokine CCL5.ConclusionsTaken together, these data suggest that α-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 α-TEA and its effect on the immune system and may prove useful in designing immune-stimulating strategies to boost the antitumor effects of α-TEA in breast cancer patients.
Highlights
Over the past several years, vitamin E a-tocopherol (a-TOH) analogs (VEA) have been evaluated for their antitumor activities
We demonstrate that a-tocopheryloxyacetic acid (a-TEA) increased the frequencies of activated CD4+ and CD8+ T cells in the tumor microenvironment, induced a tumor-specific cytotoxic lymphocyte response and resulted in higher CD4+-to-regulatory T cell (Treg) and CD8+-to-Treg ratios, as well as that the a-TEA-mediated antitumor effect was dependent on the T cell response. a-TEA treatment modulated the intratumoral cytokine and chemokine milieus
This reduction in tumor size became apparent after ~8 days of a-TEA treatment (Figure 1B) and resulted in a 1.6-fold reduction in average tumor area compared with mice on a control diet (P = 0.0006)
Summary
Over the past several years, vitamin E a-tocopherol (a-TOH) analogs (VEA) have been evaluated for their antitumor activities Of these analogs, a-tocopheryl succinate (a-TOS) and a-tocopheryloxyacetic acid (a-TEA) have been the most studied [1,2,3,4,5,6,7,8,9]. We have shown that these VEAs synergize with ex vivo generated dendritic cells (DCs) to inhibit the growth of established primary mammary tumors and suppress the formation of spontaneously arising metastases [17,26,27] This finding led us to hypothesize that the in vivo antitumor effects of a-TEA may have an immune component. This knowledge that a-TEA can stimulate the immune system while directly killing tumor cells may prove useful in designing combination immunotherapy strategies to boost the antitumor effects of a-TEA in breast cancer patients
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