Iron and Ferritin Modulate MHC Class I Expression and NK Cell Recognition

Abstract

The ability of pathogens to sequester iron from their host cells and proteins affects their virulence. Moreover, iron is required for various innate host defense mechanisms as well as for acquired immune responses. Therefore, intracellular iron concentration may influence the interplay between pathogens and immune system. Here, we investigated whether changes in iron concentrations and intracellular ferritin heavy chain (FTH) abundance may modulate the expression of Major Histocompatibility Complex molecules (MHC), and susceptibility to Natural Killer (NK) cell cytotoxicity. FTH downregulation, either by shRNA transfection or iron chelation, led to MHC surface reduction in primary cancer cells and macrophages. On the contrary, mouse embryonic fibroblasts (MEFs) from NCOA4 null mice accumulated FTH for ferritinophagy impairment and displayed MHC class I cell surface overexpression. Low iron concentration, but not FTH, interfered with IFN-γ receptor signaling, preventing the increase of MHC-class I molecules on the membrane by obstructing STAT1 phosphorylation and nuclear translocation. Finally, iron depletion and FTH downregulation increased the target susceptibility of both primary cancer cells and macrophages to NK cell recognition. In conclusion, the reduction of iron and FTH may influence the expression of MHC class I molecules leading to NK cells activation.

Magnetic Nanoparticles Attached to the NK Cell Surface for Tumor Targeting in Adoptive Transfer Therapies Does Not Affect Cellular Effector Functions

“…A slight increase, although not statistically significant, in NKp46 expression was also detected in APS-MNP loaded NK-92MI cells. As iron presence can alter MHC class I (58) and transferrin receptor (CD71) expression, we also assessed the expression of these markers in NK-92MI cells (Figure 2A). APS-MNP loading did not alter the expression of HLA-A,B,C, or CD71 in these cells.…”

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

“…In animal studies, macrophage-derived LCN2 stimulated lymphangiogenesis and promoted metastasis of breast tumors (160). Interestingly, high intracellular iron and FTH1 suppressed cell surface expression of major histocompatibility complex (MHC) class 1 on tumor cells and macrophages and consequently, iron depletion rendered tumor cells highly susceptible to death by natural killer (NK) cells (161). In accordance, decreasing iron in the tumor microenvironment increased the destruction of breast cancer cells by NK cells (162).…”

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“…Efforts are still needed to optimize therapies for leukemia targeting towards iron metabolism. A recent study finds that iron depletion may influence the expression of Major Histocompatibility Complex class I molecules to increase the target susceptibility of cancer cells to NK cell recognition [170]. This provides a basis to kill leukemia cells through modulating immune system by iron depletion.…”