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Reovirus Enhances Cytotoxicity of Natural Killer Cells Against Colorectal

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Reovirus Enhances Cytotoxicity of Natural Killer Cells Against Colorectal Long et al. J Transl Med (2021) 19:185 https://doi.org/10.1186/s12967-021-02853-y Journal of Translational Medicine RESEARCH Open Access Reovirus enhances cytotoxicity of natural killer cells against colorectal cancer via TLR3 pathway Shiqi Long1,2†, Yangzhuo Gu3†, Yuanyuan An1,2, Xiaojin Lin1,2, Xiaoqing Chen1,2, Xianyao Wang1,2, Chunxiang Liao1,2, Weiwei Ouyang4, Nianxue Wang2, Zhixu He1,5 and Xing Zhao1,2,3* Abstract Background: Cetuximab has been approved for use for frst-line treatment of patients with wild-type KRAS meta- static colorectal cancer (CRC). However, treatment with cetuximab has shown limited efcacy as a CRC monotherapy. In addition, natural killer (NK) cell function is known to be severely attenuated in cancer patients. The goal of this study was to develop a new strategy to enhance antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by NK cells, in combination with cetuximab against CRC cells. Methods: Ex vivo expanded NK cells were stimulated with reovirus, and reovirus-activated NK cells mediated ADCC assay were performed on CRC cells in combination with cetuximab. The synergistic antitumor efects of reovirus-acti- vated NK cells and cetuximab were tested on DLD-1 tumor-bearing mice. Finally, Toll-like receptor 3 (TLR3) knock- down in NK cells, along with chemical blockade of TLR3/dsRNA complex, and inhibition of the TLR3 downstream signaling pathway, were performed to explore the mechanisms by which reovirus enhances NK cell cytotoxicity. Results: We frst confrmed that exposure of NK cells to reovirus enhanced their cytotoxicity in a dose-dependent manner.We then investigated whether reovirus-activated NK cells exposed to cetuximab-bound CRC cells exhibited greater anti-tumor efcacy than either monotherapy. Co-culture of CRC cell lines with reovirus-activated NK cells indi- cated that NK cytotoxicity was signifcantly higher in combination with cetuximab, regardless of KRAS mutation status or EGFR expression level. We also found that reovirus activation of NK cells, in conjunction with cetuximab, resulted in signifcantly stronger anti-tumor efcacy.Finally, TLR3 knockdown, inhibition of TLR3/dsRNA complex or TBK1/IKKε demonstrated that activation of NK cells by reovirus was dependent on TLR3 and its downstream signaling pathway. Conclusions: This study demonstrated that combination treatment of reovirus-activated NK cells with cetuximab synergistically enhances their anti-tumor cytotoxicity, suggesting a strong candidate strategy for clinical treatment of CRC. Keywords: Natural killer, Reovirus, Colorectal cancer, Antibody-dependent cell-mediated cytotoxicity, Toll-like receptor 3 Background Colorectal cancer (CRC) is the third most common *Correspondence: [email protected] †Shiqi Long and Yangzhuo Gu contributed equally to this work cancer and the fourth leading cause of cancer-related 1 Center for Stem Cell and Tissue Engineering Research/School of Basic death worldwide [1, 2]. In the past two decades, signif- Medical Sciences, Guizhou Medical University, Guiyang 550004, Guizhou, cant advances have been made in the treatment of CRC, China Full list of author information is available at the end of the article including the introduction of oxiplatin, irinotecan, and © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Long et al. J Transl Med (2021) 19:185 Page 2 of 14 targeted therapeutic monoclonal antibodies (mAb) like neutralizing antibodies (NABs) [20, 21]. Terefore, we cetuximab [3, 4].Cetuximab, a chimeric immunoglobu- hypothesized that the antitumor efcacy of cetuximab lin G1(IgG1) mAb that targets the epidermal growth could be improved by combination with reovirus acti- factor receptor (EGFR), was approved for use in combi- vation of NK cells. In this strategy, NK cells are frst nation with FOLFIRI for frst-line treatment of patients activated with reovirus, followed by exposure of the with wild-type KRAS metastatic CRC [5].Cetuximab spe- reovirus-activated NK cells to cetuximab-bound CRC cifcally binds to EGFR,to block the endogenous EGFR cells. Using multiple CRC cell lines with diferent KRAS ligands and consequently disrupt EGFR-driven signal- mutation status and EGFR expression levels we found ing, leading to cell cycle arrest and apoptosis. In addi- that reovirus directly enhanced NK cell cytotoxicity,and tion to cetuximab’s direct anti-tumor efects, in vivo that, in combination with cetuximab, reovirus-acti- evidence from both murine models and clinical series vated NK cells exhibited increased CRC cell killing suggest that cetuximab exerts antitumor efects in part in vitro,regardless of KRAS mutation or EGFR expres- due to antibody-dependent cell-mediated cytotoxicity sion.Ten using human colorectal tumor xenograft mod- (ADCC) [6, 7]. ADCC is a mechanism of innate efector els, we also observed that reovirus activation of NK cells, cell immunity, initiated by the binding of receptors for in conjunction with cetuximab, provided signifcantly the Fc domain of IgG (FcγRs).FcγRs and their subclasses greater anti-tumor efects than either monotherapy. are expressed on dendritic cells (DCs), monocytes, mac- Finally, using Toll-like receptor 3 (TLR3) knockdown NK rophages, and natural killer (NK) cells. For NK cells, cells,chemical blockade of TLR3/double-stranded RNA recognition of IgG1 mAbs by FcγRIIIa (CD16) results in (dsRNA) complex,and chemical inhibition of the TLR3 enhanced NK cell degranulation, cytokine secretion, and downstream pathway, we further determined that reovi- cytotoxicity [8, 9].However, despite cetuximab’s multiple rus activation of NK cells is mediated in a TLR3 signaling mechanisms of action, responses to cetuximab are lim- pathway-dependent manner.Tese fndings of synergis- ited: only 1 in 5 patients with metastatic CRC responds tically enhanced NK cell anti-tumor activity provide a to cetuximab [10].New approaches are therefore needed viable framework for improvement of clinical strategies to enhance its efcacy. To this end, increasing the NK cell against CRC. response to cetuximab therapy could potentially enhance the efects of ADCC in CRC therapy. Materials and methods NK cells are a crucial target for cancer immunotherapy Cells, virus, and reagents since they can directly kill tumor cells without prior sen- Te murine fbroblastic cell line L929, the EGFR- sitization or major histocompatibility complex (MHC) expression CRC cell lines DLD-1 (KRAS-mutant, EGFR restriction. NK cells recognize tumor cells via activating medium), Caco-2 (KRAS-WT, EGFR high), and HT-29 receptors and inhibitory receptors. Activated NK cells (KRAS-WT, EGFR low) were obtained from the China directly kill tumor or virus-infected cells through release Center for Type Culture Collection (CCTCC) [6]. All cell of cytotoxic granules and proinfammatory cytokines. lines were cultured in MEM and RPMI-1640 (Hyclone) Recent fnding indicate that NK cells exhibit decreased supplemented with 10% fetal bovine serum (FBS, Gibco), activity, reduction in the proportion of IFN-γ secreting 1% (v/v) glutamine (Gibco) and 1% (v/v) penicillin/strep- NK cells,and predominant CD16dim/neg subpopulation in tomycin (Hyclone). All cells were maintained at 37 °C, 5% cancer patients [11, 12]. Additionally, multiple reports CO2 in a humidifed atmosphere.Reovirus type 3 Dear- found that NK cell function in cancer patients is severely ing strain was obtained from ATCC (VR-824). Reovirus attenuated [13]. Increased expression of programmed was propagated in L929 cells, and titrated with a stand- cell death protein 1(PD-1) or T cell immunoglobulin and ard plaque assay protocol for evaluating L929 cells. To mucin domain-containing molecule-3(Tim-3) on NK generate UV-inactivated reovirus. Reovirus in PBS were cells suppress NK cell cytotoxicity and correlate with exposed to UV (shortwave 254 nm) for 30 min. Te UV- poor prognosis [14–16]. Terefore, extensive studies have induced loss of reoviral replicability was confrmed with investigated diferent strategies to enhance NK cell cyto- a L929 cell viability assay.Live and UV-inactivated reovi- toxicity and thereby improve the clinical outcomes of NK rus were stored at -80 °C until use. Cetuximab (murine- cell-based immunotherapies [17–19]. human chimeric anti-EGFR, IgG1) was obtained from Here, in this work, we sought to develop a new strat- Bristol-Myers Squibb. Control IgG1 purchased from egy to enhance NK cell cytotoxicity while also improving Sigma-Aldrich.Bx795 (Sigma-Aldrich) was used to the efects of cetuximab-mediated ADCC. Our previ- inhibit TBK/IKKε,TLR3/dsRNA complex inhibitor was ous research found that reovirus can directly activate purchased from Calbiochem. Polyinosinic:polycytidylic fresh NK cells in vitro, and that reovirus-loaded NK cells acid [Poly (I:C)] HMW was obtained from InvivoGen. could deliver reovirus to tumor cells in the presence of Long et al. J Transl Med (2021) 19:185 Page 3 of 14 Ex vivo NK cell expansion reagent (Invitrogen, USA) for the indicated durations. Peripheral blood mononuclear cells (PBMCs) from Te TLR3 knockdown efcacy was confrmed by qPCR healthy donor blood were isolated by means of standard and Western Blotting analysis.
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