Host acid sphingomyelinase regulates microvascular function not tumor immunity.
Previous studies provided evidence that MCA/129 fibrosarcomas and B16 melanomas grow 2- to 4-fold faster in acid sphingomyelinase (asmase)-deficient mice than in asmase(+/+) littermates and are resistant to single-dose irradiation due to inability to mount an apoptotic response in tumor microvascular endothelium. However, others postulated the differences might be associated with a host antitumor immune response in asmase(+/+) mice that is not expressed in asmase(-/-) mice due to phenotypic deficiency in antitumor immunity. The present studies demonstrate that none of the tumor-host combinations displayed the classic criteria of an immunogenic tumor because they lacked endotumoral or peritumoral infiltrates almost entirely. Furthermore, neither MCA/129 fibrosarcoma nor B16 melanoma tumors showed differences in growth or radioresponsiveness when implanted into mutant mouse models (Rag(-/-) and MEF(-/-)) lacking functional immune cell [natural killer (NK), NK-T, T, and B cells] populations. Additionally, development and function of B-, T-, and NK-cell populations in asmase(-/-) mice were normal, indistinguishable from their wild-type littermates. These data provide definitive evidence that MCA/129 fibrosarcomas and B16F1 melanomas do not elicit a host immune response in wild-type mice and that the asmase(-/-) phenotype is not deficient in antitumor immunity, supporting the notion that the patterns of tumors growth and radiation response are conditionally linked to the ability of the tumor endothelium to undergo ASMase-mediated apoptosis.
Garcia-Barros
Monica
M
Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Lacorazza
Daniel
D
Petrie
Howard
H
Haimovitz-Friedman
Adriana
A
Cardon-Cardo
Carlos
C
Nimer
Stephen
S
Fuks
Zvi
Z
Kolesnick
Richard
R
D000818:Animals; D002196:Capillaries / Q000503:physiopathology*; D005434:Flow Cytometry; D007111:Immunity, Cellular; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism / Q000502:physiology*
D013108:Sphingomyelin Phosphodiesterase