Impaired antibody-dependent cellular cytotoxicity mediated by herceptin in patients with gastric cancer.
The humanized monoclonal antibody Herceptin, which specifically targets HER-2/neu, exhibits growth inhibitory activity against HER-2/neu-overexpressing tumors and is approved for therapeutic use with proved survival benefit in patients with HER-2/neu-positive breast cancer. In the present study, we investigated whether Herceptin could affect the HER-2/neu-overexpressing gastric cancer cells based on antibody-dependent cell-mediated cytotoxicity (ADCC) and compared immune effector cells from gastric cancer patients with normal individuals on ADCC. HER-2/neu-expressing gastric cancer cells could be killed by Herceptin-mediated ADCC and the Herceptin-induced ADCC correlated with the degree of HER-2/neu expression on the gastric cancer cells. However, the Herceptin-mediated ADCC was significantly impaired in peripheral blood mononuclear cells from advanced disease patients (n = 10) compared with that in early disease (n = 12; P = 0.04) or healthy individuals (n = 10, P = 0.02). Moreover, natural killer (NK) cells purified from patients with advanced disease indicated less Herceptin-mediated ADCC in comparison with that from healthy donors (P = 0.04), whereas monocytes purified from the patients showed an almost equal amount of Herceptin-mediated ADCC in comparison with that from healthy individuals, indicating that NK cell dysfunction contributed to the impaired Herceptin-mediated ADCC in gastric cancer patients. Furthermore, the NK-cell dysfunction on Herceptin-mediated ADCC correlated with the down-regulation of CD16zeta expression in the patients, and interleukin 2 ex vivo treatment of NK cells could restore the impairment of Herceptin-mediated ADCC, concomitant to the normalization of the expression of CD16zeta molecules. Thus, some modalities such as interleukin 2 treatment aimed at reversing NK dysfunction may be necessary for successful Herceptin treatment of gastric cancer.
Kono
Koji
K
First Department of Surgery, Yamanashi Medical University, Japan. kojikono@res.yamanashi-med.ac.jp
Takahashi
Akihiro
A
Ichihara
Fumiko
F
Sugai
Hidemitsu
H
Fujii
Hideki
H
Matsumoto
Yoshirou
Y
D000230:Adenocarcinoma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D013274:Stomach Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007376:Interleukin-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab