Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment
| العنوان: | Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment |
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| المؤلفون: | Bradley Heidrich, Yingzhe Li, Leopoldo Luistro, Mcdaid Ronan, Priyanka Nair-Gupta, Kathryn Packman, Francois Gaudet, Stephen I. Rudnick, Jocelin Joseph, Melissa Smith, Ricardo Attar, Kodandaram Pillarisetti |
| المصدر: | Blood Cancer Journal, Vol 10, Iss 6, Pp 1-13 (2020) Blood Cancer Journal |
| بيانات النشر: | Nature Publishing Group, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Cancer microenvironment, 0301 basic medicine, Stromal cell, CD3 Complex, T-Lymphocytes, T cell, Interleukin-3 Receptor alpha Subunit, Integrin alpha4beta1, lcsh:RC254-282, Article, Mice, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, Bone Marrow, Cell Line, Tumor, Antibodies, Bispecific, Tumor Microenvironment, Animals, Humans, Medicine, B-Cell Maturation Antigen, Tumor microenvironment, business.industry, Hematology, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Leukemia, Myeloid, Acute, Leukemia, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Tumour immunology, Female, Blinatumomab, Bone marrow, Stem cell, Multiple Myeloma, business, medicine.drug |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 2044-5385 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cbf4db86f2a278c0a1b39c9066bba2c8 http://link.springer.com/article/10.1038/s41408-020-0331-4 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....cbf4db86f2a278c0a1b39c9066bba2c8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20445385 |
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