Decreased Iron in Cancer Cells and Their Microenvironment Improves Cytolysis of Breast Cancer Cells by Natural Killer Cells.

The association of iron with anticancer immunity is unclear. In order to determine the role of iron in anticancer immunity, we manipulated intracellular iron levels of the human MCF-7 and MDA-MB-231 breast cancer cell lines, and measured cytolysis of breast cancer cells by the natural killer cell line NK-92MI, nitric oxide (NO) production, tumor necrosis factor alpha (TNFα) production and gene expression of ferritin heavy chain (FTH1). We found that NK-92MI increased synthesis and release of NO and TNFα into the medium during co-culturing of NK-92MI cells with MCF-7 or MDA-MB-231 cells. Addition of iron inhibited the cytolysis of the breast cancer cell lines. The iron chelator deferoxamine (DFOM) increased NK-92MI cytolysis to MCF-7 or MDA-MB-231 cells. Iron reversed cytotoxicity to breast cancer cells induced by NO, released from S-nitroso-N-acetyl-penicillamine (NO donor). Real time quantitative polymerase chain reaction showed that iron up-regulated the expression of FTH1 and iron chelator DFOM reduced FTH1 expression of MCF-7 and MDA-MB-231 cells. In conclusion, increased iron in cancer cells and their microenvironment protects cancer cells from natural killer cell cytolysis by antagonizing NO- and TNFα-associated cytotoxicity and by up-regulation of ferritin expression in breast cancer cells. Conversely, a decrease in iron concentration caused by DFOM improves natural killer cytolysis of tumor cells.