α-Tocopheryloxyacetic acid: A novel chemotherapeutic that stimulates the antitumor immune response

Tobias Hahn, Bhumasamudram Jagadish, Eugene A Mash, Kendra Garrison, Emmanuel T. Akporiaye

Research output: Contribution to journalArticle

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Abstract

Introduction: α-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.Methods: Because 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.Results: α-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.Conclusions: Taken 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.

Original languageEnglish (US)
Article numberR4
JournalBreast Cancer Research
Volume13
Issue number1
DOIs
StatePublished - Jan 13 2011

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Acids
Neoplasms
T-Lymphocytes
Interferons
Breast Neoplasms
Cytokines
Chemokine CCL5
CD4-CD8 Ratio
Tumor Microenvironment
Tocopherols
Regulatory T-Lymphocytes
Cellular Structures
Therapeutics
Growth
Chemokines
Heterografts
Interleukin-4
Ether
Immune System
Rodentia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

α-Tocopheryloxyacetic acid : A novel chemotherapeutic that stimulates the antitumor immune response. / Hahn, Tobias; Jagadish, Bhumasamudram; Mash, Eugene A; Garrison, Kendra; Akporiaye, Emmanuel T.

In: Breast Cancer Research, Vol. 13, No. 1, R4, 13.01.2011.

Research output: Contribution to journalArticle

Hahn, Tobias ; Jagadish, Bhumasamudram ; Mash, Eugene A ; Garrison, Kendra ; Akporiaye, Emmanuel T. / α-Tocopheryloxyacetic acid : A novel chemotherapeutic that stimulates the antitumor immune response. In: Breast Cancer Research. 2011 ; Vol. 13, No. 1.
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abstract = "Introduction: α-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.Methods: Because 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.Results: α-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.Conclusions: Taken 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.",
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