Table 1.

Advantages and limitations of common immunodeficient and humanized mouse models used in studies of NK cells in tumor immunity

Mouse strain/model	Murine NK cells	Human NK cells	Engraftment of solid tumor cell lines, Engraftment of primary tumors	Engraftment of hematologic malignancies, Engraftment of normal hematopoietic cells	Advantages	Limitations	Ref.
Athymic nude	+++	−	+, ±	−, −	Well-characterized, hairless, s.c. tumors are easy to assess	Intact humoral adaptive system and innate immune system Very limited engraftment mainly due to high NK cell activity	[21, 64]
C.B17-scid	++	−	+, +	±, ±	Allows for engraftment of a broader range of human solid tumors compared to nude mice	Intact innate immune system: normal antigen presentation, myeloid cell development, and NK cell functions Limited engraftment due to remaining NK cell activity “Leakiness” in older mice –production of small numbers of mature T and B cells	[18, 22, 65]
NOD-scid	+ (Defective)	−	++, ++	+, +	Allows for engraftment of large numbers of solid tumors and hematological malignancies.	Some tumors fail to engraft or grow efficiently, mainly due to remaining NK cell activity “Leakiness” of residual T and B cells Mice develop thymic lymphomas by 8–9 months, not suitable for long-term studies Sensitivity to radiation	[23–26]
NSG	−	−	+++, +++	++, +++	Profoundly immunodeficient Allows for engraftment of a variety of solid tumors and blood cancers Allows for engraftment and differentiation of human hematopoietic stem cells into multi-lineage subsets Best strain for humanization	Human cell engraftment is better in newborns compared to adults. Sensitivity to radiation	[27–29, 66]
CD34+ hu-NSG	−	+ (not fully functional, decreased NK cell receptors)	+++, +++ (PDX)	++, +++	Permits differentiation of all major human blood cell types including NK cells Stable, long-term engraftment Allows for growth of non-HLA-matched CSC-like tumors Can be used for testing cancer immunotherapeutics	Human NK cells are present in low numbers and they require IL-15/IL-15Rα to increase function T cells are selected in the context of mouse MHC Sensitivity to radiation Limited mucosal immunity	([28, 29, 38, 43–46, 54], data not published)
Hu-BLT hu-NSG	−	+ (not fully functional, decreased NK cell receptors)	+++, not determined	Not determined, +++	Permits differentiation of all major human blood cell types including NK cells T cells are HLA-restricted Mucosal and adaptive immune functions Allows for growth of non-HLA-matched CSC-like tumors Best available model for testing cancer immunotherapeutics in the context of fully reconstituted human immune system	Human NK cells are detected in low numbers Fetal tissue accessibility Surgical procedure required More prone to GvHD than CD34+ humanized model Sensitivity to radiation	([28, 33, 34, 39], data not published)