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Targeting NKG2DL with Bispecific NKG2D–CD16 and NKG2D–CD3 Fusion Proteins on Triple–Negative Breast Cancer

Triple–negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with a poor response rate to conventional systemic treatment and high relapse rates. Members of the natural killer group 2D ligand (NKG2DL) family are expressed on cancer cells but are typically absent from he...

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Autores principales: Kaidun, Polina, Holzmayer, Samuel J., Greiner, Sarah M., Seller, Anna, Tegeler, Christian M., Hagelstein, Ilona, Mauermann, Jonas, Engler, Tobias, Koch, André, Hartkopf, Andreas D., Salih, Helmut R., Märklin, Melanie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10487695/
https://www.ncbi.nlm.nih.gov/pubmed/37685962
http://dx.doi.org/10.3390/ijms241713156
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author Kaidun, Polina
Holzmayer, Samuel J.
Greiner, Sarah M.
Seller, Anna
Tegeler, Christian M.
Hagelstein, Ilona
Mauermann, Jonas
Engler, Tobias
Koch, André
Hartkopf, Andreas D.
Salih, Helmut R.
Märklin, Melanie
author_facet Kaidun, Polina
Holzmayer, Samuel J.
Greiner, Sarah M.
Seller, Anna
Tegeler, Christian M.
Hagelstein, Ilona
Mauermann, Jonas
Engler, Tobias
Koch, André
Hartkopf, Andreas D.
Salih, Helmut R.
Märklin, Melanie
author_sort Kaidun, Polina
collection PubMed
description Triple–negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with a poor response rate to conventional systemic treatment and high relapse rates. Members of the natural killer group 2D ligand (NKG2DL) family are expressed on cancer cells but are typically absent from healthy tissues; thus, they are promising tumor antigens for novel immunotherapeutic approaches. We developed bispecific fusion proteins (BFPs) consisting of the NKG2D receptor domain targeting multiple NKG2DLs, fused to either anti–CD3 (NKG2D–CD3) or anti–CD16 (NKG2D–CD16) Fab fragments. First, we characterized the expression of the NKG2DLs (MICA, MICB, ULBP1–4) on TNBC cell lines and observed the highest surface expression for MICA and ULBP2. Targeting TNBC cells with NKG2D–CD3/CD16 efficiently activated both NK and T cells, leading to their degranulation and cytokine release and lysis of TNBC cells. Furthermore, PBMCs from TNBC patients currently undergoing chemotherapy showed significantly higher NK and T cell activation and tumor cell lysis when stimulated with NKG2D–CD3/CD16. In conclusions, BFPs activate and direct the NK and T cells of healthy and TNBC patients against TNBC cells, leading to efficient eradication of tumor cells. Therefore, NKG2D–based NK and T cell engagers could be a valuable addition to the treatment options for TNBC patients.
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spelling pubmed-104876952023-09-09 Targeting NKG2DL with Bispecific NKG2D–CD16 and NKG2D–CD3 Fusion Proteins on Triple–Negative Breast Cancer Kaidun, Polina Holzmayer, Samuel J. Greiner, Sarah M. Seller, Anna Tegeler, Christian M. Hagelstein, Ilona Mauermann, Jonas Engler, Tobias Koch, André Hartkopf, Andreas D. Salih, Helmut R. Märklin, Melanie Int J Mol Sci Article Triple–negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with a poor response rate to conventional systemic treatment and high relapse rates. Members of the natural killer group 2D ligand (NKG2DL) family are expressed on cancer cells but are typically absent from healthy tissues; thus, they are promising tumor antigens for novel immunotherapeutic approaches. We developed bispecific fusion proteins (BFPs) consisting of the NKG2D receptor domain targeting multiple NKG2DLs, fused to either anti–CD3 (NKG2D–CD3) or anti–CD16 (NKG2D–CD16) Fab fragments. First, we characterized the expression of the NKG2DLs (MICA, MICB, ULBP1–4) on TNBC cell lines and observed the highest surface expression for MICA and ULBP2. Targeting TNBC cells with NKG2D–CD3/CD16 efficiently activated both NK and T cells, leading to their degranulation and cytokine release and lysis of TNBC cells. Furthermore, PBMCs from TNBC patients currently undergoing chemotherapy showed significantly higher NK and T cell activation and tumor cell lysis when stimulated with NKG2D–CD3/CD16. In conclusions, BFPs activate and direct the NK and T cells of healthy and TNBC patients against TNBC cells, leading to efficient eradication of tumor cells. Therefore, NKG2D–based NK and T cell engagers could be a valuable addition to the treatment options for TNBC patients. MDPI 2023-08-24 /pmc/articles/PMC10487695/ /pubmed/37685962 http://dx.doi.org/10.3390/ijms241713156 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kaidun, Polina
Holzmayer, Samuel J.
Greiner, Sarah M.
Seller, Anna
Tegeler, Christian M.
Hagelstein, Ilona
Mauermann, Jonas
Engler, Tobias
Koch, André
Hartkopf, Andreas D.
Salih, Helmut R.
Märklin, Melanie
Targeting NKG2DL with Bispecific NKG2D–CD16 and NKG2D–CD3 Fusion Proteins on Triple–Negative Breast Cancer
title Targeting NKG2DL with Bispecific NKG2D–CD16 and NKG2D–CD3 Fusion Proteins on Triple–Negative Breast Cancer
title_full Targeting NKG2DL with Bispecific NKG2D–CD16 and NKG2D–CD3 Fusion Proteins on Triple–Negative Breast Cancer
title_fullStr Targeting NKG2DL with Bispecific NKG2D–CD16 and NKG2D–CD3 Fusion Proteins on Triple–Negative Breast Cancer
title_full_unstemmed Targeting NKG2DL with Bispecific NKG2D–CD16 and NKG2D–CD3 Fusion Proteins on Triple–Negative Breast Cancer
title_short Targeting NKG2DL with Bispecific NKG2D–CD16 and NKG2D–CD3 Fusion Proteins on Triple–Negative Breast Cancer
title_sort targeting nkg2dl with bispecific nkg2d–cd16 and nkg2d–cd3 fusion proteins on triple–negative breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10487695/
https://www.ncbi.nlm.nih.gov/pubmed/37685962
http://dx.doi.org/10.3390/ijms241713156
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