Mice with a Targeted Mutation in Lymphotoxin-α Exhibit Enhanced Tumor Growth and Metastasis: Impaired NK Cell Development and Recruitment

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Abstract
Mice deficient in lymphotoxin (LT)-α lack peripheral lymph nodes and Peyer’s patches and have profound defects in development of follicular dendritic cell networks, germinal center formation, and T/B cell segregation in the spleen. Although LTα is known to be expressed by NK cells as well as T and B lymphocytes, the requirement of LTα for NK cell functions is largely unknown. To address this issue, we have assessed NK cell functions in LTα-deficient mice by evaluating tumor models with known requirements for NK cells to control their growth and metastasis. Syngeneic B16F10 melanoma cells inoculated s.c. grew more rapidly in LTα−/− mice than in the wild-type littermates, and the formation of experimental pulmonary metastases was significantly enhanced in LTα−/− mice. Although LTα−/− mice exhibited almost a normal total number of NK cells in spleen, they showed an impaired recruitment of NK cells to lung and liver. Additionally, lytic NK cells were not efficiently produced from LTα−/− bone marrow cells in vitro in the presence of IL-2 and IL-15. These data suggest that LTα signaling may be involved in the maturation and recruitment of NK cells and may play an important role in antitumor surveillance.