Perforin is a major contributor to NK cell control of tumor metastasis.
We provide the first demonstration, using experimental and spontaneous models of metastasis in C57BL/6 (B6) (RM-1 prostate carcinoma) and BALB/c (DA3 mammary carcinoma) mice, that tumor metastasis is primarily controlled by perforin-dependent cytotoxicity mediated by NK1.1+ cells. MHC class Ilow RM-1 and DA3 tumor cells were sensitive in vitro to Fas-mediated lysis or spleen NK cells in a perforin-dependent fashion. Perforin-deficient NK cells did not lyse these tumors, and perforin-deficient mice were 10-100-fold less proficient than wild-type mice in rejecting the metastasis of tumor cells to the lung. Fas ligand mutant gld mice displayed uncompromised protection against tumor metastasis. Depletion of NK subsets resulted in greater numbers of metastases than observed in perforin-deficient mice, suggesting that perforin-independent effector functions of NK cells may also contribute to protection from tumor metastasis.
Smyth
M J
MJ
Cellular Immunity Laboratory, Austin Research Institute, Heidelberg, Victoria, Australia. m.smyth@ari.unibelb.edu.au
Thia
K Y
KY
Cretney
E
E
Kelly
J M
JM
Snook
M B
MB
Forbes
C A
CA
Scalzo
A A
AA
D000818:Animals; D000941:Antigens / Q000096:biosynthesis; D000950:Antigens, Ly; D000954:Antigens, Surface; D002277:Carcinoma / Q000276:immunology* / Q000473:pathology / Q000556:secondary*; D002455:Cell Division / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000276:immunology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055651:NK Cell Lectin-Like Receptor Subfamily B; D009368:Neoplasm Transplantation; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011471:Prostatic Neoplasms / Q000276:immunology; D014176:Protein Biosynthesis; D011506:Proteins; D014407:Tumor Cells, Cultured / Q000637:transplantation
D000941:Antigens; D000950:Antigens, Ly; D000954:Antigens, Surface; D015395:Histocompatibility Antigens Class I; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D055651:NK Cell Lectin-Like Receptor Subfamily B; D052899:Pore Forming Cytotoxic Proteins; D011506:Proteins; D054353:Perforin