Immunodeficient Mouse Strains Display Marked Variability in Growth of Human Melanoma Lung Metastases

Purpose: Immunodeficient mice serve as critical hosts for transplantation of xenogeneic cells for in vivo analysis of various biological processes. Because investigators typically select one or two immunodeficient mouse strains as recipients, no comprehensive study has been published documenting differences in human tumor engraftment. Taking advantage of the increased metastatic potential of RhoC-expressing human (A375) melanoma cells, we evaluate four immunodeficient mouse strains: severe combined immunodeficiency (scid), nonobese diabetic (NOD)-scid, NOD-scid beta 2m(null), and NOD-scid IL2R gamma(null) as xenograft tumor recipients. Experimental Design: Bioluminescence, magnetic resonance imaging, and histopathology were used to monitor serial tumor growth. Natural killer (NK) cell function was examined in each mouse strain using standard (51)Chromium release assays. Results: Melanoma metastases growth is delayed and variable in scid and NOD-scid mice. In contrast, NOD-scid beta 2m(null) and NOD-scid IL2R gamma(null) mice show rapid tumor engraftment, although tumor growth is variable in NOD-scid beta 2m(null) mice. NK cells were detected in all strains except NOD-scid IL2R gamma(null), and in vitro activated scid, NOD-scid, and NOD-scid beta 2m(null) NK cells kill human melanoma lines and primary melanoma cells. Expression of human NKG2D ligands MHC class I chain-related A and B molecules renders melanoma susceptible to murine NK cell-mediated cytotoxicity and killing is inhibited by antibody blockade of murine NKG2D. Conclusions: Murine NKG2D recognition of MICA/B is an important receptor-ligand interaction used by NK cells in immunodeficient strains to limit engraftment of human tumors. The absolute NK deficiency in NOD-scid IL2R gamma(null) animals makes this strain an excellent recipient of melanoma and potentially other human malignancies.