Decreased NK Cells in Patients with Head and Neck Cancer Determined in Archival DNA

AbstractFailed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the presence of immunosuppressive myeloid populations. Here we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth inhibition and a reduction in myeloid cells endogenously expressing high levels of PD-L1. Treatment of xenograft tumors resulted in PD-L1 dependent tumor growth inhibition. PD-L1 CAR haNKs reduced levels of macrophages and other myeloid cells endogenously expressing high PD-L1 in peripheral blood from patients with head and neck cancer. The clinical study of PD-L1 CAR haNKs is warranted.

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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 ◽

10.3390/ijms222011057 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11057

Author(s):

Mandy Gruijs ◽

Sonja H. Ganzevles ◽

Marijke Stigter-van Walsum ◽

Richard van der Mast ◽

Monique M. van Ostaijen-ten Dam ◽

...

Keyword(s):

Head And Neck Cancer ◽

Nk Cells ◽

Head And Neck ◽

Neck Cancer ◽

Combination Treatment ◽

Nk Cell ◽

Checkpoint Inhibition ◽

Toll Like Receptor

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.

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PD-1 is a marker of activation on tumor infiltrating NK cells in head and neck cancer

Journal for ImmunoTherapy of Cancer ◽

10.1186/2051-1426-3-s2-p398 ◽

2015 ◽

Vol 3 (S2) ◽

Cited By ~ 4

Author(s):

Fernando Concha-Benavente ◽

Raghvendra M Srivastava ◽

Benjamin Kansy ◽

Robert L Ferris

Keyword(s):

Head And Neck Cancer ◽

Nk Cells ◽

Head And Neck ◽

Neck Cancer

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Abstract 127: Exosomes derived from head and neck cancer enhance the cytotoxicities of NK cells by NAP1-IRF-3 pathway

10.1158/1538-7445.am2018-127 ◽

2018 ◽

Author(s):

Wantao Chen ◽

Yingnan Wang ◽

Jianjun Zhang

Keyword(s):

Head And Neck Cancer ◽

Nk Cells ◽

Head And Neck ◽

Neck Cancer

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Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells

eLife ◽

10.7554/elife.54854 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 2

Author(s):

Yvette Robbins ◽

Sarah Greene ◽

Jay Friedman ◽

Paul E Clavijo ◽

Carter Van Waes ◽

...

Keyword(s):

Head And Neck Cancer ◽

Growth Inhibition ◽

Nk Cells ◽

Head And Neck ◽

Neck Cancer ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

Myeloid Cells ◽

Tumor Rejection ◽

Tumor Control

Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the presence of immunosuppressive myeloid populations. Here, we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth inhibition and a reduction in myeloid cells endogenously expressing high levels of PD-L1. Treatment of xenograft tumors resulted in PD-L1-dependent tumor growth inhibition. PD-L1 CAR haNKs reduced levels of macrophages and other myeloid cells endogenously expressing high PD-L1 in peripheral blood from patients with head and neck cancer. The clinical study of PD-L1 CAR haNKs is warranted.

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