The breast tumor microenvironment alters the phenotype and function of natural killer cells

Cell Mol Immunol. 2016 Sep;13(5):628-39. doi: 10.1038/cmi.2015.42. Epub 2015 Aug 17.


Natural killer (NK) cells are innate immune cells with the ability to identify and eliminate transformed cells. However, within tumors, many studies have described NK cells as non-functional. The developmental stage of tumor-associated NK cells and how this may relate to functionality has not been explored. We examined the developmental state of NK cells from polyoma middle T antigen (pyMT) transgenic mouse (MMTV-pMT) breast tumors. In pyMT tumors, NK cells were immature as evidenced by their decreased expression of DX5 and their CD27(low)CD11b(low) phenotype. These immature NK cells also had increased expression of NKG2A and expressed low levels of NKp46, perforin, and granzyme B. In contrast, splenic NK cells isolated from the same mice maintained their maturity and their expression of activation markers. To delineate whether the tumor microenvironment directly alters NK cells, we adoptively transferred labeled NK cells and followed their activation status in both the spleen and the tumor. NK cells that arrived at the tumor had half the expression of NKp46 within three days of transfer in comparison to those which arrived at the spleen. In an effort to modify the tumor microenvironment and assess the plasticity of intratumoral NK cells, we treated pyMT tumors with IL-12 and anti-TGF-β. After one week of treatment, the maturity of tumor-associated NK cells was increased; thus, indicating that these cells possess the ability to mature and become activated. A better understanding of how NK cells are modified by the tumor microenvironment will help to develop strategies aimed at bolstering immune responses against tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, CD / metabolism
  • Antigens, Ly / metabolism
  • Antigens, Polyomavirus Transforming / metabolism
  • Cell Differentiation
  • Female
  • Granzymes / metabolism
  • Interleukin-12 / metabolism
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / pathology*
  • Lymphocyte Activation / immunology
  • Mammary Neoplasms, Animal / pathology*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NK Cell Lectin-Like Receptor Subfamily C / metabolism
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism
  • Natural Cytotoxicity Triggering Receptor 1 / metabolism
  • Perforin / metabolism
  • Phenotype
  • Spleen / pathology
  • Transforming Growth Factor beta / metabolism
  • Tumor Microenvironment*


  • Antigens, CD
  • Antigens, Ly
  • Antigens, Polyomavirus Transforming
  • Klrk1 protein, mouse
  • NK Cell Lectin-Like Receptor Subfamily C
  • NK Cell Lectin-Like Receptor Subfamily K
  • Natural Cytotoxicity Triggering Receptor 1
  • Ncr1 protein, mouse
  • Transforming Growth Factor beta
  • Perforin
  • Interleukin-12
  • Granzymes