Anti-CD137 monoclonal antibody enhances trastuzumab-induced, natural killer cell-mediated cytotoxicity against pancreatic cancer cell lines with low human epidermal growth factor-like receptor 2 expression

• Published in: PloS one 2018-12, Vol.13 (12), p.e0200664-e0200664
• Main Authors: Masu, Takushi, Atsukawa, Masanori, Nakatsuka, Katsuhisa, Shimizu, Masumi, Miura, Daishu, Arai, Taeang, Harimoto, Hirotomo, Kondo, Chisa, Kaneko, Keiko, Futagami, Seiji, Kawamoto, Chiaki, Takahashi, Hidemi, Iwakiri, Katsuhiko
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Immunological - immunology; Antineoplastic Agents, Immunological - pharmacology; Biology and life sciences; Biotechnology; Breast cancer; Cancer; Cancer therapies; CD137 antigen; Cell Line, Tumor; Chemotherapy; Cytotoxicity; Epidermal growth factor; ErbB-2 protein; Flow cytometry; Gastroenterology; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - immunology; Gene polymorphism; Growth factors; Hepatology; Humans; Immunity, Cellular - drug effects; Immunoglobulins; Immunology; Immunotherapy; Internal medicine; Killer Cells, Natural - immunology; Killer Cells, Natural - pathology; Medical prognosis; Medical schools; Medicine; Medicine and health sciences; Methods; Monoclonal antibodies; Natural killer cells; Pancreatic cancer; Pancreatic carcinoma; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Penicillin; Polymorphism; Polymorphism, Genetic; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - immunology; Receptors, IgG - genetics; Receptors, IgG - immunology; Research and Analysis Methods; Supplements; Targeted cancer therapy; Toxicity; Trastuzumab; Trastuzumab - pharmacology; Tumor cell lines; Tumor Necrosis Factor Receptor Superfamily, Member 9 - antagonists & inhibitors; Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0200664

Because human epidermal growth factor-like receptor (HER) 2 is expressed on the surface of human pancreatic carcinoma cells to varying degrees, trastuzumab, an anti-HER2 monoclonal antibody (mAb), is expected to exert antibody-dependent, natural killer (NK) cell-mediated cytotoxicity (ADCC) against the cells. However, some reports found that the effect of trastuzumab against human pancreatic carcinoma cells was limited because most express only limited HER2. We examined whether anti-CD137 stimulating mAb could enhance trastuzumab-mediated ADCC against Panc-1, a human pancreatic cancer cell line with low HER2 expression, in vitro. Supplementation of anti-CD137 mAb could improve trastuzumab-mediated ADCC against Panc-1 which was insufficient without this stimulating antibody. The ADCC differed in individual cells, and this was related to the expression of CD137 on the surface of NK cells after trastuzumab stimulation in association with the Fcγ-RIIIA polymorphism. NK cells with Fcγ-RIIIA-VV/VF showed high levels of ADCC against Panc-1, but those with Fcγ-RIIIA-FF did not show optimal ADCC. In addition, trastuzumab-mediated ADCC against the human pancreatic cancer cell line Capan-1 with high HER2 expression was generally high and not affected by the Fcγ-RIIIA polymorphism. These results demonstrated that in Fcγ-RIIIA-VV/VF-carrying healthy individuals, trastuzumab plus αCD137 mAb could induce effective ADCC against HER2-low-expressing pancreatic cancer cell lines, and that such an approach may result in similar findings in patients with pancreatic cancer.