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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| Format: | Article |
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MDPI AG
2021-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/20/11057 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Mandy Gruijs |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T06:30:47Z |
| format | Article |
| id | doaj.art-6f8f7fa11cc640268ebbcabbe9372eb7 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:30:47Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6f8f7fa11cc640268ebbcabbe9372eb72023-11-22T18:33:09ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122201105710.3390/ijms222011057NK 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 ModelsMandy Gruijs0Sonja H. Ganzevles1Marijke Stigter-van Walsum2Richard van der Mast3Monique M. van Ostaijen-ten Dam4Cornelis W. Tuk5Marco W. Schilham6C. René Leemans7Ruud H. Brakenhoff8Marjolein van Egmond9Rieneke van de Ven10Jantine E. Bakema11Amsterdam 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 NetherlandsAmsterdam 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 NetherlandsAmsterdam 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 NetherlandsAmsterdam 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 NetherlandsLeiden University Medical Center, Department of Pediatrics, Albinusdreef 2, 2333 ZA Leiden, The NetherlandsAmsterdam 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 NetherlandsLeiden University Medical Center, Department of Pediatrics, Albinusdreef 2, 2333 ZA Leiden, The NetherlandsAmsterdam 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 NetherlandsAmsterdam 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 NetherlandsAmsterdam 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 NetherlandsAmsterdam 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 NetherlandsAmsterdam 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 NetherlandsThe 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.https://www.mdpi.com/1422-0067/22/20/11057head and neck cancerimmunotherapycetuximabTLR agonistsNK cellsantibody-dependent cellular cytotoxicity |
| spellingShingle | 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 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 head and neck cancer immunotherapy cetuximab TLR agonists NK cells antibody-dependent cellular cytotoxicity |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | head and neck cancer immunotherapy cetuximab TLR agonists NK cells antibody-dependent cellular cytotoxicity |
| url | https://www.mdpi.com/1422-0067/22/20/11057 |
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