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Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment

Redirecting T cells to specifically kill malignant cells has been validated as an effective anti-cancer strategy in the clinic with the approval of blinatumomab for acute lymphoblastic leukemia. However, the immunosuppressive nature of the tumor microenvironment potentially poses a significant hurdl...

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Autores principales: Nair-Gupta, Priyanka, Rudnick, Stephen I., Luistro, Leopoldo, Smith, Melissa, McDaid, Ronan, Li, Yingzhe, Pillarisetti, Kodandaram, Joseph, Jocelin, Heidrich, Bradley, Packman, Kathryn, Attar, Ricardo, Gaudet, François
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264144/
https://www.ncbi.nlm.nih.gov/pubmed/32483120
http://dx.doi.org/10.1038/s41408-020-0331-4
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author Nair-Gupta, Priyanka
Rudnick, Stephen I.
Luistro, Leopoldo
Smith, Melissa
McDaid, Ronan
Li, Yingzhe
Pillarisetti, Kodandaram
Joseph, Jocelin
Heidrich, Bradley
Packman, Kathryn
Attar, Ricardo
Gaudet, François
author_facet Nair-Gupta, Priyanka
Rudnick, Stephen I.
Luistro, Leopoldo
Smith, Melissa
McDaid, Ronan
Li, Yingzhe
Pillarisetti, Kodandaram
Joseph, Jocelin
Heidrich, Bradley
Packman, Kathryn
Attar, Ricardo
Gaudet, François
author_sort Nair-Gupta, Priyanka
collection PubMed
description Redirecting T cells to specifically kill malignant cells has been validated as an effective anti-cancer strategy in the clinic with the approval of blinatumomab for acute lymphoblastic leukemia. However, the immunosuppressive nature of the tumor microenvironment potentially poses a significant hurdle to T cell therapies. In hematological malignancies, the bone marrow (BM) niche is protective to leukemic stem cells and has minimized the efficacy of several anti-cancer drugs. In this study, we investigated the impact of the BM microenvironment on T cell redirection. Using bispecific antibodies targeting specific tumor antigens (CD123 and BCMA) and CD3, we observed that co-culture of acute myeloid leukemia or multiple myeloma cells with BM stromal cells protected tumor cells from bispecific antibody-T cell-mediated lysis in vitro and in vivo. Impaired CD3 redirection cytotoxicity was correlated with reduced T cell effector responses and cell–cell contact with stromal cells was implicated in reducing T cell activation and conferring protection of cancer cells. Finally, blocking the VLA4 adhesion pathway in combination with CD3 redirection reduced the stromal-mediated inhibition of cytotoxicity and T cell activation. Our results lend support to inhibiting VLA4 interactions along with administering CD3 redirection therapeutics as a novel combinatorial regimen for robust anti-cancer responses.
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spelling pubmed-72641442020-06-10 Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment Nair-Gupta, Priyanka Rudnick, Stephen I. Luistro, Leopoldo Smith, Melissa McDaid, Ronan Li, Yingzhe Pillarisetti, Kodandaram Joseph, Jocelin Heidrich, Bradley Packman, Kathryn Attar, Ricardo Gaudet, François Blood Cancer J Article Redirecting T cells to specifically kill malignant cells has been validated as an effective anti-cancer strategy in the clinic with the approval of blinatumomab for acute lymphoblastic leukemia. However, the immunosuppressive nature of the tumor microenvironment potentially poses a significant hurdle to T cell therapies. In hematological malignancies, the bone marrow (BM) niche is protective to leukemic stem cells and has minimized the efficacy of several anti-cancer drugs. In this study, we investigated the impact of the BM microenvironment on T cell redirection. Using bispecific antibodies targeting specific tumor antigens (CD123 and BCMA) and CD3, we observed that co-culture of acute myeloid leukemia or multiple myeloma cells with BM stromal cells protected tumor cells from bispecific antibody-T cell-mediated lysis in vitro and in vivo. Impaired CD3 redirection cytotoxicity was correlated with reduced T cell effector responses and cell–cell contact with stromal cells was implicated in reducing T cell activation and conferring protection of cancer cells. Finally, blocking the VLA4 adhesion pathway in combination with CD3 redirection reduced the stromal-mediated inhibition of cytotoxicity and T cell activation. Our results lend support to inhibiting VLA4 interactions along with administering CD3 redirection therapeutics as a novel combinatorial regimen for robust anti-cancer responses. Nature Publishing Group UK 2020-06-01 /pmc/articles/PMC7264144/ /pubmed/32483120 http://dx.doi.org/10.1038/s41408-020-0331-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Nair-Gupta, Priyanka
Rudnick, Stephen I.
Luistro, Leopoldo
Smith, Melissa
McDaid, Ronan
Li, Yingzhe
Pillarisetti, Kodandaram
Joseph, Jocelin
Heidrich, Bradley
Packman, Kathryn
Attar, Ricardo
Gaudet, François
Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment
title Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment
title_full Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment
title_fullStr Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment
title_full_unstemmed Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment
title_short Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment
title_sort blockade of vla4 sensitizes leukemic and myeloma tumor cells to cd3 redirection in the bone marrow microenvironment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264144/
https://www.ncbi.nlm.nih.gov/pubmed/32483120
http://dx.doi.org/10.1038/s41408-020-0331-4
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