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Article

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

1
Amsterdam UMC, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam—Amsterdam Institute for Infection and Immunity, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
2
Amsterdam UMC, Department of Otolaryngology-Head and Neck Surgery, Cancer Center Amsterdam—Amsterdam Institute for Infection and Immunity, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
3
Leiden University Medical Center, Department of Pediatrics, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
4
Amsterdam UMC, Department of Surgery, Cancer Center Amsterdam, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
*
Author to whom correspondence should be addressed.
Shared authorship.
Shared authorship.
§
Current affiliation: Genmab BV, Uppsalalaan 15, 3584 CT Utrecht, The Netherlands.
Academic Editor: Ji-Yoon Noh
Int. J. Mol. Sci. 2021, 22(20), 11057; https://doi.org/10.3390/ijms222011057
Received: 21 September 2021 / Revised: 6 October 2021 / Accepted: 8 October 2021 / Published: 14 October 2021
(This article belongs to the Special Issue Natural Killer Cells and Immunotherapy)
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. View Full-Text
Keywords: head and neck cancer; immunotherapy; cetuximab; TLR agonists; NK cells; antibody-dependent cellular cytotoxicity; immunosuppression head and neck cancer; immunotherapy; cetuximab; TLR agonists; NK cells; antibody-dependent cellular cytotoxicity; immunosuppression
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MDPI and ACS Style

Gruijs, M.; Ganzevles, S.H.; Stigter-van Walsum, M.; van der Mast, R.; van Ostaijen-ten Dam, M.M.; Tuk, C.W.; Schilham, M.W.; Leemans, C.R.; Brakenhoff, R.H.; van Egmond, M.; van de Ven, R.; Bakema, J.E. 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. Int. J. Mol. Sci. 2021, 22, 11057. https://doi.org/10.3390/ijms222011057

AMA Style

Gruijs M, Ganzevles SH, Stigter-van Walsum M, van der Mast R, van Ostaijen-ten Dam MM, Tuk CW, Schilham MW, Leemans CR, Brakenhoff RH, van Egmond M, van de Ven R, Bakema JE. 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. International Journal of Molecular Sciences. 2021; 22(20):11057. https://doi.org/10.3390/ijms222011057

Chicago/Turabian Style

Gruijs, Mandy, Sonja H. Ganzevles, Marijke Stigter-van Walsum, Richard van der Mast, Monique M. van Ostaijen-ten Dam, Cornelis W. Tuk, Marco W. Schilham, C. R. Leemans, Ruud H. Brakenhoff, Marjolein van Egmond, Rieneke van de Ven, and Jantine E. Bakema 2021. "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" International Journal of Molecular Sciences 22, no. 20: 11057. https://doi.org/10.3390/ijms222011057

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