TY - JOUR
T1 - α-Tocopheryloxyacetic acid
T2 - A novel chemotherapeutic that stimulates the antitumor immune response
AU - Hahn, Tobias
AU - Jagadish, Bhumasamudram
AU - Mash, Eugene A.
AU - Garrison, Kendra
AU - Akporiaye, Emmanuel T.
N1 - Funding Information:
We acknowledge the help of the Immune Monitoring Laboratory at the Earle A. Chiles Research Institute. In particular we thank Dan Haley for the development of multiparameter flow cytometry panels and William Miller for flow cytometric analysis. Furthermore, we thank Alexandra Borodovsky for technical help and Magdalena Polanczyk for critical review of the manuscript. This work was supported by grants from the National Institutes of Health (grant NIH 5R01CA120552) and the American Institute for Cancer Research (grant 07A126) to ETA. EAM and BJ were supported by grants from the National Institutes of Health (NIH grant CA23074).
PY - 2011/1/13
Y1 - 2011/1/13
N2 - 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.
AB - 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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U2 - 10.1186/bcr2808
DO - 10.1186/bcr2808
M3 - Article
C2 - 21232138
AN - SCOPUS:84860390351
SN - 1465-5411
VL - 13
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 1
M1 - R4
ER -