Natural killer cell cytolytic activity is necessary for in vivo antitumor activity of the dipeptide L-glutamyl-L-tryptophan.
A dipeptide, L-glutamyl L-tryptophan (L-glu-L-trp), was identified in a screen for immunomodulators in the soluble fraction of the thymus. L-glu-L-trp inhibits tumor growth in mice without showing direct cellular toxicity in a variety of human tumor cell lines. L-glu-L-trp antitumor activity in vivo requires the presence of natural killer (NK) cells. Defective trafficking of cytoplasmic granules caused by the Lyst mutation also resulted in loss of antitumor activity of the dipeptide. The effect of L-glu-L-trp on tumor growth in mice with targeted gene mutations demonstrated the absolute requirement for perforin for antitumor activity. The requirement of 2 major modulators of NK cell activity, gamma interferon (IFNgamma) and interleukin (IL)-12, were also tested. L-glu-L-trp had full antitumor activity in IFNgamma knockout mice, but had significantly diminished activity in IL-12 knockout mice. These data show that L-glu-L-trp antitumor activity in mice is dependent on cytolytic cell activity of NK or NKT cells. L-glu-L-trp in vivo regulates NK cell function independent of IFNgamma but partly dependent on IL-12.
Smith
D Lynne
DL
University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Cai
Jie
J
University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Zhu
SuTao
S
University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Wei
Wen
W
University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Fukumoto
Jon
J
University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Sharma
Sanjai
S
University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Masood
Rizwan
R
University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Gill
Parkash S
PS
University of Southern California Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003594:Cytoplasmic Granules / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004151:Dipeptides / Q000627:therapeutic use*; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013601:T-Lymphocytes / Q000502:physiology; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D004151:Dipeptides; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; C060736:thymogen; D054353:Perforin; D018664:Interleukin-12; D007371:Interferon-gamma