Abstract
BackgroundCD137 is a target for tumor immunotherapy. However, the role of CD137 in gastric cancer (GC), especially in inducing GC cell apoptosis, has not been studied.MethodsFoxp3+ and CD8+ T cells in GCs were investigated using immunohistochemistry (IHC). CD137 expression in GCs was detected using flow cytometry, IHC and immunofluorescence (IF). Peripheral blood mononuclear cells (PBMCs) and CD8+ T cells isolated from peripheral blood were stimulated with a CD137 agonist in vitro. CD8+ T cell proliferation and p65 expression was examined using flow cytometry. P65 nuclear translocation was analyzed using IF. IL-10, TGF-β, IFN-γ, perforin and granzyme B were detected using real-time quantitative PCR (real-time PCR). PBMCs and primary GC cells were cocultured and stimulated with a CD137 agonist in vitro. Apoptosis of primary GC cells was detected using flow cytometry.ResultsOur data demonstrated that GC tumors showed characteristics of an immunosuppressive microenvironment. CD137 was predominantly expressed in CD8+ T cells in GCs and had a positive correlation with tumor cell differentiation. The CD137 agonist promoted CD8+ T cell proliferation and increased the secretion of IFN-γ, perforin and granzyme B, which induced primary GC cell apoptosis. Mechanistically, this study found that the CD137 agonist induced NF-κB nuclear translocation in CD8+ T cells.ConclusionOur results demonstrated that a CD137 agonist induced primary GC cell apoptosis by enhancing CD8+ T cells via activation of NF-κB signaling.
Highlights
CD137 is a target for tumor immunotherapy
Poor infiltration of C D8+ T cells but accumulation of Tregs in GCs It is well known that C D8+ T cells in gastric cancer tissues are favorable for prognosis of GC patients and Foxp3+ Tregs are negatively associated with survival of GC patients
To compare the composition of C D8+ and Treg cells in the tumor tissues, tumor-free tissues and tumor margin tissues of GC patients, we analyzed the proportions of CD8+ T cells and Foxp3+ Tregs using IHC. Foxp3+ Tregs accumulated in the tumor (Fig. 1a and b), but most CD8+ T cells sequestered at the tumor margin and in tumor-free tissues (Fig. 1c and d)
Summary
CD137 is a target for tumor immunotherapy. The role of CD137 in gastric cancer (GC), espe‐ cially in inducing GC cell apoptosis, has not been studied. Gastric cancer (GC) is a common malignant tumor. Chemotherapy and molecular-targeted therapy achieved limited improvements in survival [1, 2]. Immunotherapy is a new method of tumor treatment in addition to surgery, chemotherapy and radiotherapy [3, 4]. Therapeutic vaccines activate the initial T lymphocyte reaction, and enhances the activity of T lymphocytes [5]. Adaptive immunotherapy achieved an antitumor effect via the reinfusion of tumor-specific effector lymphocytes expanded in vitro [6]. Immunosuppressive agents showed a certain effect in the
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