Natural killer (NK) cells are components of innate immunity and key effectors against tumor cells. The natural-killer group 2, member D (NKG2D) is a stimulatory receptor expressed on NK cells, NKT cells, and subsets of γδ+T cells. The ligands of NKG2D are expressed on the surface of transformed cancer cells (lung, pancreas, kidney). Radiation therapy (RT) may upregulate the expression of NKG2D ligands. In humans, these ligands were reported as major histocompatibility (MIC) A, MIC B , and UL-16 binding protein (ULBP) 1-6. The NKG2D ligands expressed on tumor cell surface upon binding to NKG2D activates NK cells. The NKG2D ligands expressed on the tumor cell surface are shed by metalloproteases (abundantly present in cancer) and released as soluble forms. ULBP2, a NKG2D ligand, is expressed in various tumor tissues and released into soluble form by sheddases, ADAM 10 and 17 (a-disintergin and metalloproteinase 10 and 17), which are also upregulated on the tumor cell surface.
Our preliminary data shows that gamma RT leads to increased expression and release of soluble sULBP2 from multiple human types of cancer cell lines into the supernatant (lung, pancreas, kidney), which may interfere with NK-mediated killing of tumor cells. Our research will determine the underlying mechanisms and avenues to manipulate them with the final goal of increasing RT’s efficacy in activating NK cells against tumor cells.