Research Article: Stimulation of natural killer cells with rhCD137 ligand enhances tumor-targeting antibody efficacy in gastric cancer

Date Published: October 15, 2018

Publisher: Public Library of Science

Author(s): Toshihiro Misumi, Kazuaki Tanabe, Nobuaki Fujikuni, Hideki Ohdan, Pier Giorgio Petronini.

http://doi.org/10.1371/journal.pone.0204880

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.

Partial Text

Gastric cancer remains the fifth most common malignancy and the third leading cause of cancer death worldwide [1]. Although its global incidence is declining, it remains highly prevalent in Asian countries, such as China, Korea, and Japan [1, 2]. The prognosis of patients with gastric cancer has been improved by early detection and surgical resection with regional lymphadenectomy; however, the mortality associated with advanced gastric cancer remains high and is mainly a result of recurrence and metastasis. 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 [3–5]. However, these results have been mostly unsatisfactory, and more active treatment strategies are required to improve outcomes for gastric cancer patients.

The prognosis of patients with advanced gastric cancer remains poor due to the lack of effective chemotherapeutics and tumor-targeted antibodies [9, 25]. Manipulation of co-stimulatory immune molecules represents a new and attractive strategy for improving therapeutic efficacies. Immunomodulatory antibodies, such as CTLA-4-, PD-1-, and PD-L1-specific mAbs, target the patient immune system to overcome immunosuppression induced by tumor cells and generate an antitumor immune response [26]. Clinical data validate mAb-mediated cancer immunotherapy as a valuable therapeutic strategy, and recently, a clinical trial of gastric cancer patients was conducted using an anti-PD-1 mAb, reporting its ability to significantly prolong overall survival of gastric cancer patients and reduce the risk of death by 37% as compared with placebos [27]. In addition to expanding the clinical benefits of this approach, agents designed to target other immunomodulatory pathways are currently under evaluation, including co-stimulatory molecules, such as CD134 and CD137 [28]. In this study, we hypothesized that CD137 stimulation would enhance the antitumor activity of NK cells against gastric cancer cells. To test this hypothesis, we first confirmed that trastuzumab- or cetuximab-coated gastric cancer cells were capable of inducing CD137 expression in NK cells, followed by confirmation that CD137 stimulation using rhCD137L enhanced NK cell cytotoxicity and the release of cytokines toward mAb-coated tumor cells. Moreover, we demonstrated that CD137 expression was dependent upon differences in IgG subclass and FcγRIIIA polymorphisms.

The results of our study suggested that CD137 stimulation enhanced the anti-gastric-cancer effects of trastuzumab and cetuximab, and that CD137 expression was dependent upon mAb-binding affinity with Fc structures and FcγRIIIA polymorphisms. Our results supported those reported previously and indicated possible applicability to gastric cancer. These results provided insight into additional avenues for exploiting the power of NK cells for gastric cancer immunotherapy.

 

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http://doi.org/10.1371/journal.pone.0204880

 

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