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

Mandy Gruijs, Sonja H. Ganzevles, Marijke Stigter-Van Walsum, Richard van der Mast, Monique M. van Ostaijen-Ten Dam, Cornelis W. Tuk, Marco W. Schilham, C. René Leemans, Ruud H. Brakenhoff, Marjolein van Egmond, Rieneke van de Ven, Jantine E. Bakema

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4 Citations (Scopus)


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.

Original languageEnglish
Article number11057
JournalInternational journal of molecular sciences
Issue number20
Publication statusPublished - 1 Oct 2021


  • Antibody-dependent cellular cytotoxicity
  • Cetuximab
  • Head and neck cancer
  • Immunosuppression
  • Immunotherapy
  • NK cells
  • TLR agonists

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