title: Overexpression of IL-15 promotes tumor destruction via NK1.1+ cells in a spontaneous breast cancer model.
abstract: BACKGROUND
  Natural Killer (NK) cells play an important role in tumor prevention, but once tumors form, the numbers as well as the cytotoxic functions of NK cells are reduced. IL-15 is a cytokine that increases and activates NK cells. Here we will examine the anti-tumor role of IL-15 in a spontaneous breast cancer model.
  
  
  METHODS
  To achieve this, Polyoma Middle T (MT) mice that form spontaneous breast cancer were crossed with mice that either overexpress IL-15 (IL-15 transgenic (TG)) or mice that lack IL-15 (IL-15 knockout (KO)). We compared survival curves and tumor formation in IL-15 KO/MT, MT and IL-15 TG/MT groups. In addition, the phenotype, activation and contribution of NK cells and CD8 T cells to tumor formation were examined in each of these mouse strains via flow cytometry, ELISA, adoptive transfer and antibody depletion experiments.
  
  
  RESULTS
  IL-15KO/MT tumors formed and progressed to endpoint more quickly than MT tumors. These tumors displayed little apoptosis and poor CD8 T cell infiltration. In contrast, IL-15 TG/MT mice had increased survival and the tumors displayed extensive cell death, high proportions of activated NK cells and a higher infiltration of CD8 T cells than MT tumors. CD8 T cells in IL-15 TG/MT tumors were capable of secreting IFNγ, possessed markers of memory, did not display an exhausted phenotype and were frequently NK1.1+. Long-term antibody depletion studies in IL-15 TG/MT mice revealed that NK1.1+, but not CD8 T cells, were critical for tumor destruction. Lastly, human NK cells, when exposed to a similar cytokine environment as that found in IL-15TG/MT tumors, were capable of killing human breast cancer cells.
  
  
  CONCLUSIONS
  This study reveals that high levels of IL-15 can promote tumor destruction and reduce metastasis in breast cancer via effects on NK1.1+ cells. Our results suggest that strategies aimed at increasing NK cell activation may be effective against solid epithelial cancers.
authors: Department of Pathology and Molecular Medicine, McMaster Immunology Research Center (MIRC), McMaster University, Hamilton, Canada. gillgra@mcmaster.ca.
authors: Amy E
authors: AE
authors: Gillgrass
authors: Department of Pathology and Molecular Medicine, McMaster Immunology Research Center (MIRC), McMaster University, Hamilton, Canada. chewm@univmail.cis.mcmaster.ca.
authors: Marianne V
authors: MV
authors: Chew
authors: Department of Pathology and Molecular Medicine, McMaster Immunology Research Center (MIRC), McMaster University, Hamilton, Canada. tamara.krneta1@gmail.com.
authors: Tamara
authors: T
authors: Krneta
authors: Department of Pathology and Molecular Medicine, McMaster Immunology Research Center (MIRC), McMaster University, Hamilton, Canada. ashkara@mcmaster.ca.
authors: Ali A
authors: AA
authors: Ashkar
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000556:secondary; D008213:Lymphocyte Activation; D015674:Mammary Neoplasms, Animal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D019409:Interleukin-15; C527211:Klrb1c protein, mouse; D055651:NK Cell Lectin-Like Receptor Subfamily B