دورية أكاديمية
Expression of modified FcγRI enables myeloid cells to elicit robust tumor-specific cytotoxicity.
العنوان: | Expression of modified FcγRI enables myeloid cells to elicit robust tumor-specific cytotoxicity. |
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المؤلفون: | Farhat-Younis L; Department of Pathology, School of Medicine, Tel Aviv University, Tel Aviv, Israel., Na M; Department of Pathology, School of Medicine, Tel Aviv University, Tel Aviv, Israel., Zarfin A; Department of Pathology, School of Medicine, Tel Aviv University, Tel Aviv, Israel., Khateeb A; Department of Pathology, School of Medicine, Tel Aviv University, Tel Aviv, Israel., Santana-Magal N; Department of Pathology, School of Medicine, Tel Aviv University, Tel Aviv, Israel., Richter A; Department of Pathology, School of Medicine, Tel Aviv University, Tel Aviv, Israel., Gutwillig A; Department of Pathology, School of Medicine, Tel Aviv University, Tel Aviv, Israel., Rasoulouniriana D; Department of Pathology, School of Medicine, Tel Aviv University, Tel Aviv, Israel., Gleiberman A; Department of Pathology, School of Medicine, Tel Aviv University, Tel Aviv, Israel., Beck L; Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel., Giger T; Department of Molecular Cell Biology, Weizmann Institute, Rehovot, Israel., Ashkenazi A; Department of Cell and Developmental Biology, School of Medicine, Tel Aviv University, Tel Aviv, Israel., Barzel A; Department of Biochemistry Molecular Biology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel., Rider P; Department of Pathology, School of Medicine, Tel Aviv University, Tel Aviv, Israel., Carmi Y; Department of Pathology, School of Medicine, Tel Aviv University, Tel Aviv, Israel. |
المصدر: | ELife [Elife] 2024 Jun 17; Vol. 12. Date of Electronic Publication: 2024 Jun 17. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012- |
مواضيع طبية MeSH: | Receptors, IgG*/metabolism , Receptors, IgG*/immunology , Myeloid Cells*/immunology , Myeloid Cells*/metabolism, Animals ; Mice ; Mice, Inbred C57BL ; Cell Line, Tumor ; Cytotoxicity, Immunologic ; Immunoglobulin M/metabolism ; Immunoglobulin M/immunology ; Signal Transduction ; Macrophages/immunology ; Macrophages/metabolism ; Neoplasms/immunology |
مستخلص: | Despite the central role of T cells in tumor immunity, attempts to harness their cytotoxic capacity as a therapy have met limited efficacy, partially as a result of the suppressive microenvironment which limits their migration and activation. In contrast, myeloid cells massively infiltrate tumors and are well adapted to survive these harsh conditions. While they are equipped with cell-killing abilities, they often adopt an immunosuppressive phenotype upon migration to tumors. Therefore, the questions of how to modify their activation programming against cancer, and what signaling cascades should be activated in myeloid cells to elicit their cytotoxicity have remained unclear. Here, we found that activation of IgM-induced signaling in murine myeloid cells results in secretion of lytic granules and massive tumor cell death. These findings open venues for designing novel immunotherapy by equipping monocytes with chimeric receptors that target tumor antigens and consequently, signal through IgM receptor. Nonetheless, we found that myeloid cells do not express the antibody-derived portion used to recognize the tumor antigen due to the induction of an ER stress response. To overcome this limitation, we designed chimeric receptors that are based on the high-affinity FcγRI for IgG. Incubation of macrophages expressing these receptors along with tumor-binding IgG induced massive tumor cell killing and secretion of reactive oxygen species and Granzyme B. Overall, this work highlights the challenges involved in genetically reprogramming the signaling in myeloid cells and provides a framework for endowing myeloid cells with antigen-specific cytotoxicity. Competing Interests: LF, MN, AZ, AK, NS, AR, AG, AG, LB, TG, AA, AB No competing interests declared, DR This paper was funded by Gilboa Therapeutics where Diana Rasoulouniriana is a shareholder, PR This paper was funded by Gilboa Therapeutics where Peleg Rider is a shareholder, YC This paper was funded by Gilboa Therapeutics where Yaron Carmi is a shareholder (© 2023, Farhat-Younis et al.) |
التعليقات: | Erratum in: Elife. 2024 Jul 02;13:e101165. doi: 10.7554/eLife.101165. (PMID: 38953289) |
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فهرسة مساهمة: | Keywords: ER stress; chimeric antigen receptor; immunology; immunotherapy; inflammation; mouse; myeloid cells |
المشرفين على المادة: | 0 (Receptors, IgG) 0 (Immunoglobulin M) |
تواريخ الأحداث: | Date Created: 20240617 Date Completed: 20240617 Latest Revision: 20240702 |
رمز التحديث: | 20240702 |
مُعرف محوري في PubMed: | PMC11182644 |
DOI: | 10.7554/eLife.91999 |
PMID: | 38885133 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2050-084X |
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DOI: | 10.7554/eLife.91999 |