Abstract
Although many anticancer agents for gastric cancer have been developed, the prognosis for many patients remains poor. Recently, costimulatory immune molecules that reactivate antitumor immune responses by utilizing the host immune system have attracted attention as new therapeutic strategies. CD137 is a costimulatory molecule that reportedly potentiates the antitumor activity of tumor-targeting monoclonal antibodies (mAbs) by enhancing antibody-dependent cellular cytotoxicity. However, it remains unclear whether CD137 stimulates tumor-regulatory activity in gastric cancer. In this study, we investigated the antitumor effects of CD137 stimulation on gastric cancer cells administered tumor-targeting mAbs. Our results showed that human natural killer (NK) cells were activated by expressing CD137 after encountering trastuzumab-coated gastric cancer cells, and that stimulation of activated NK cells in the presence of trastuzumab and recombinant human CD137 ligand (rhCD137L) enhanced cytotoxicity and release of cytokines (IFN-γ, TNF, granzyme A, or granzyme B) as compared with activated NK cells with trastuzumab alone (p < 0.05). By combination treatment with rhCD137L, similar effects were obtained regarding cancer cell cytotoxicity in the presence of cetuximab (p < 0.01). Moreover, we revealed that CD137 expression was dependent upon the affinity between the Fc portion of the antibodies and FcγRIIIa of NK cells based on results indicating that human IgG1 and IgG3 subclasses enhanced CD137 expression (p < 0.001). These results confirmed that FcγRIIIA polymorphisms (158 V/V) enhanced CD137 expression to a greater degree than 158 F polymorphisms (p = 0.014). Our results suggested that CD137 stimulation could promote the effects of tumor-targeting mAbs in gastric cancer, and that further investigation of antibody binding affinity and in vivo activities might improve therapeutic strategies related to the treatment of gastric cancer patients.
Highlights
Gastric cancer remains the fifth most common malignancy and the third leading cause of cancer death worldwide [1]
Purified natural killer (NK) cells from healthy human patients were incubated with various human epidermal growth factor receptor 2 (HER2)-expressing gastric cancer cell lines (Fig 1A) in the presence of trastuzumab or rituximab
Incubation with the combination of trastuzumab and gastric cancer cell lines resulted in significantly upregulated CD137 expression and presentation on NK cells compared with the combination of rituximab and gastric cancer cell lines
Summary
Gastric cancer remains the fifth most common malignancy and the third leading cause of cancer death worldwide [1]. The expected survival period of untreated stage IV gastric cancer is reportedly 3 to 5 months, and systemic chemotherapy alone has been reported to extend overall survival by up to 9 to 13 months [3,4,5]. These results have been mostly unsatisfactory, and more active treatment strategies are required to improve outcomes for gastric cancer patients
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