title: α-Tocopheryloxyacetic acid: a novel chemotherapeutic that stimulates the antitumor immune response.
abstract: BACKGROUND
  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.
authors.affiliation: Robert W Franz Cancer Research Center, Earle A Chiles Research Institute, Providence Portland Medical Center, 4805 NE Glisan Street, Portland, OR 97213, USA. tobias.hahn@providence.org
authors.forename: Tobias
authors.initials: T
authors.lastname: Hahn
authors.forename: Bhumasamudram
authors.initials: B
authors.lastname: Jagadish
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Mash
authors.forename: Kendra
authors.initials: K
authors.lastname: Garrison
authors.forename: Emmanuel T
authors.initials: ET
authors.lastname: Akporiaye
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D024505:Tocopherols / Q000008:administration & dosage / Q000494:pharmacology*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; C488288:2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid; D024505:Tocopherols