ArticleJournal of translational medicine2021
Reovirus enhances cytotoxicity of natural killer cells against colorectal cancer via TLR3 pathway.
Article in Journal of translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Tumour-associated dsRNA accumulation and innate immune activation: mechanistic basis and therapeutic strategies.EBioMedicine · 2026Review
- Natural killer cell-based immunotherapies for colorectal cancer: Current strategies, challenges, and future perspectives.World journal of gastroenterology · 2025Review
- Toll-like receptors in health and disease.MedComm · 2024Review
- Review
- Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality.Frontiers in immunology · 2023Article
- The Latest Approach of Immunotherapy with Endosomal TLR Agonists Improving NK Cell Function: An Overview.Biomedicines · 2022Review
- Article
- NK Cell-Based Immunotherapy in Colorectal Cancer.Vaccines · 2022Review
- Emerging role of RNA sensors in tumor microenvironment and immunotherapy.Journal of hematology & oncology · 2022Review
- NK cell-derived exosomes enhance the anti-tumor effects against ovarian cancer by delivering cisplatin and reactivating NK cell functions.Frontiers in immunology · 2022Article
- Integrated Analysis of Necroptosis-Related Genes for Prognosis, Immune Microenvironment Infiltration, and Drug Sensitivity in Colon Cancer.Frontiers in medicine · 2022Article
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Authors and funding
11 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundCetuximab has been approved for use for first-line treatment of patients with wild-type KRAS metastatic colorectal cancer (CRC). However, treatment with cetuximab has shown limited efficacy 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.
methodsEx 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 effects of reovirus-activated NK cells and cetuximab were tested on DLD-1 tumor-bearing mice. Finally, Toll-like receptor 3 (TLR3) knockdown 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.
resultsWe first confirmed 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 efficacy than either monotherapy. Co-culture of CRC cell lines with reovirus-activated NK cells indicated that NK cytotoxicity was significantly 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 significantly stronger anti-tumor efficacy.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.
conclusionsThis 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.
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