title: The Antitumor Efficacy of IL2/IL21-Cultured Polyfunctional Neu-Specific T Cells Is TNFα/IL17 Dependent.
abstract: Infusion of HER2-specific T cells, derived from vaccine-primed patients and expanded with IL2/IL12, has induced tumor regression in a minority of patients with metastatic treatment-refractory HER2(+) breast cancer. We questioned whether alteration of cytokine growth factors used to culture vaccine-primed T cells could improve antitumor activity.
  
  
  
  Using the TgMMTV-neu murine mammary tumor model, we cultured T cells derived from mice immunized with a previously defined neu class II peptide, p98-114 (neu p98), and evaluated different cytokine combinations for expansion.
  
  
  
  Infusion of neu p98-specific T-cell lines derived from all cytokine conditions evaluated resulted in significant antitumor activity compared with infused naïve splenocytes (P < 0.05). T cells cultured with IL2/IL21 could uniquely mediate complete regression of spontaneous mammary tumors. IL2/IL21 cultured neu-specific T cells demonstrated a different cytokine secretion pattern as compared with other cultured T cells; secreting high levels of TNFα and IL17 (P < 0.05). Moreover, tumor-infiltrating CD8(+) cells were significantly increased after the infusion of IL2/IL21 cultured T cells as compared with tumors treated with T cells expanded under other cytokine conditions (P < 0.001). The antitumor effect of the infusion of IL2/IL21 cultured cells was mediated by CD8 T cells. Depletion of TNFα or IL17, but not IFNγ, abrogated the tumor growth inhibition induced by the IL2/IL21 T cells and markedly decreased the influx of CD8 into tumors. Finally, IL2/IL21-cultured human antigen specific T cells also displayed a similar polyfunctional Th1/Th17 phenotype.
  
  
  
  Expansion of HER2 vaccine-primed T cells with IL2/IL21 may have the potential to effectively mediate tumor regression when used in adoptive transfer. Clin Cancer Res; 22(9); 2207-16. ©2015 AACR.
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington.
authors.forename: Vy
authors.initials: V
authors.lastname: Phan-Lai
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington.
authors.forename: Yushe
authors.initials: Y
authors.lastname: Dang
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington.
authors.forename: Ekram
authors.initials: E
authors.lastname: Gad
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Childs
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington. ndisis@uw.edu.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology*; D007378:Interleukins / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines; D020381:Interleukin-17; D007376:Interleukin-2; D007378:Interleukins; D018719:Erb-b2 Receptor Tyrosine Kinases; D014409:Tumor Necrosis Factor-alpha; D000098546:Interleukin-21