Table 1.

Mechanisms of immune escape and drugs used with their effects on NK cells in hematological malignancies.

Hematological malignancies	Principal mechanisms of escape	References	Principal class of drugs used	Effects of drugs on NK activation	References
MDS	NK-cell quantitative deficiency Elevated TNF	(13, 14, 49)	Demethylating agents IMIDs	Up-regulation of KIR and NKG2D ligands	(76, 81)
				NKp46 upregulation
AML	Upregulation of HLA-I Decrease expression of NKp30, 2B4/CD244 Production of ROS	(9, 19, 39, 40, 54)	HDACIs Histamine dihydrochloride All-trans retinoic acid Monoclonal antibody (IPH2101)	Upregulation of MICA/B expression	(65, 67, 72, 73, 84, 85)
				Suppress ROS production
				Promote NK-cells cytotoxicity
CLL	Upregulation of HLA-I low level of MICA or ULBP	(18, 37)	Monoclonal antibody	Mediate NK-cells cytotoxicity	(88)
MM	Production of sMICA/sMICB Weak expression of CD16	(30, 31)	IMIDs Proteasome inhibitor IPH2101	NKp46 upregulation NKG2D ligand upregulation	(79, 82–84, 86)
CML	Production of sMICA and weak expression of NKG2D	(29)	Tyrosine kinase inhibitor	sMICA down-regulation and NKG2D upregulation	(29)
ALL	Low production of MICA/B and ULBP	(26, 27, 41)
	Down regulation of HLA-A and HLA-Bw6

MDS, myelodysplastic syndrome; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; MM, multiple myeloma; CML, chronic myelogenous leukemia; ALL, acute lymphoblastic leukemia; s/MICA/B, soluble/stress-induced molecules human class I-like molecules A and B; ULBPs, UL-16 binding proteins; ROS, reactive oxygen species; KIR, killer immunoglobulin-like receptors; PDGF, platelet-derived growth factor; HDC, histamine dihydrochloride; IMIDs, immune-modulatory drugs; HDACIs, Histone deacetylase inhibitors.