How to exploit stress-related immunity against Hodgkin’s lymphoma: Targeting ERp5 and ADAM sheddases

Stress-related immunity can be activated in the course of lymphoproliferative disorders, including Hodgkin’s lymphoma, upon the interaction between killer cell lectin-like receptor subfamily K, member 1 (KLRK1, best known as NKG2D) on effector lymphocytes and NKG2D ligands (NKG2DL), such as MHC class I polypeptide-related sequence A (MICA), MICB and various UL16-binding proteins (ULBPs), on lymphoma cells. However, NKG2DLs can also bind NKG2D upon shedding, thus affecting the recognition of lymphoma cells by the immune system. The proteolytic cleavage of MICA depends on protein disulfide isomerase family A, member 6 (PDIA6, a thiol isomerase best known as ERp5) as well as on the disintegrins and metalloproteinases ADAM metallopeptidase domain 10 (ADAM10) and ADAM17, which also cleave ULPBs. These enzymes can be targeted in novel therapeutic schemes to avoid the escape of malignant cells from stress-evoked immune responses.