NK Cell-Dependent Antibody-Mediated Immunotherapy Is Improved In Vitro and In Vivo When Combined with Agonists for Toll-like Receptor 2 in Head and Neck Cancer Models

The immunosuppressive character of head and neck cancers may explain the relatively low response rates to antibody therapy targeting a tumor antigen, such as cetuximab, and anti-PD-1 checkpoint inhibition. Immunostimulatory agents that overcome tumor-derived inhibitory signals could augment therapeu...

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Bibliographic Details
Published in:	International journal of molecular sciences Vol. 22; no. 20; p. 11057
Main Authors:	Gruijs, Mandy, Ganzevles, Sonja H., Stigter-van Walsum, Marijke, van der Mast, Richard, van Ostaijen-ten Dam, Monique M., Tuk, Cornelis W., Schilham, Marco W., Leemans, C. René, Brakenhoff, Ruud H., van Egmond, Marjolein, van de Ven, Rieneke, Bakema, Jantine E.
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 14.10.2021 MDPI
Subjects:	Agonists Animals Antibodies Antibody-Dependent Cell Cytotoxicity - immunology Binding sites Cancer Cell Line, Tumor Cetuximab - pharmacology Cetuximab - therapeutic use Chemotherapy Cytokines Cytokines - metabolism Cytotoxicity Drug Therapy, Combination Experiments FDA approval Female Growth factors Head & neck cancer Head and Neck Neoplasms - therapy Human papillomavirus Humans Immunotherapy Killer Cells, Natural - immunology Leukocytes, Mononuclear - cytology Leukocytes, Mononuclear - drug effects Leukocytes, Mononuclear - metabolism Ligands Lipopeptides - pharmacology Lipopeptides - therapeutic use Mice Mice, Nude Monoclonal antibodies Radiation therapy Receptors, IgG - agonists Receptors, IgG - metabolism Targeted cancer therapy Toll-Like Receptor 2 - agonists Toll-Like Receptor 2 - metabolism Transplantation, Heterologous NK cells antibody-dependent cellular cytotoxicity TLR agonists head and neck cancer immunotherapy cetuximab immunosuppression
ISSN:	1422-0067, 1661-6596, 1422-0067
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Summary:	The immunosuppressive character of head and neck cancers may explain the relatively low response rates to antibody therapy targeting a tumor antigen, such as cetuximab, and anti-PD-1 checkpoint inhibition. Immunostimulatory agents that overcome tumor-derived inhibitory signals could augment therapeutic efficacy, thereby enhancing tumor elimination and improving patient survival. Here, we demonstrate that cetuximab treatment combined with immunostimulatory agonists for Toll-like receptor (TLR) 2 induces profound immune responses. Natural killer (NK) cells, isolated from healthy individuals or patients with head and neck cancer, harbored enhanced cytotoxic capacity and increased tumor-killing potential in vitro. Additionally, combination treatment increased the release of several pro-inflammatory cytokines and chemokines by NK cells. Tumor-bearing mice that received cetuximab and the TLR2 ligand Pam3CSK4 showed increased infiltration of immune cells into the tumors compared to mice that received cetuximab monotherapy, resulting in a significant delay in tumor growth or even complete tumor regression. Moreover, combination treatment resulted in improved overall survival in vivo. In conclusion, combining tumor-targeting antibody-based immunotherapy with TLR stimulation represents a promising treatment strategy to improve the clinical outcomes of cancer patients. This treatment could well be applied together with other therapeutic strategies such as anti-PD-(L)1 checkpoint inhibition to further overcome immunosuppression.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Current affiliation: Genmab BV, Uppsalalaan 15, 3584 CT Utrecht, The Netherlands. Shared authorship.
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms222011057