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Natural killer cell cytolytic activity is necessary for in vivo antitumor activity of the dipeptide L‐glutamyl‐L‐tryptophan
Author(s) -
Smith D. Lynne,
Cai Jie,
Zhu SuTao,
Wei Wen,
Fukumoto Jon,
Sharma Sanjai,
Masood Rizwan,
Gill Parkash S.
Publication year - 2003
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.11253
Subject(s) - in vivo , cytolysis , natural killer cell , biology , dipeptide , perforin , knockout mouse , microbiology and biotechnology , in vitro , cytotoxicity , biochemistry , amino acid , gene , genetics
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 (IFNγ) and interleukin (IL)‐12, were also tested. L‐glu‐L‐trp had full antitumor activity in IFNγ 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 IFNγ but partly dependent on IL‐12. © 2003 Wiley‐Liss, Inc.