دورية أكاديمية
أعرض في EDS

CXCR4 has a dual role in improving the efficacy of BCMA-redirected CAR-NK cells in multiple myeloma.

التفاصيل البيبلوغرافية
العنوان: CXCR4 has a dual role in improving the efficacy of BCMA-redirected CAR-NK cells in multiple myeloma.
المؤلفون: Moles MW; Translational Tumorimmunology, Max Delbrück Center, Berlin, Germany., Erdlei H; Translational Tumorimmunology, Max Delbrück Center, Berlin, Germany., Menzel L; Translational Tumorimmunology, Max Delbrück Center, Berlin, Germany., Massaro M; Microenvironmental Regulation in Autoimmunity and Cancer, Max Delbrück Center, Berlin, Germany., Fiori A; Translational Tumorimmunology, Max Delbrück Center, Berlin, Germany., Bunse M; Microenvironmental Regulation in Autoimmunity and Cancer, Max Delbrück Center, Berlin, Germany., Schrimpf M; Translational Tumorimmunology, Max Delbrück Center, Berlin, Germany., Gerlach K; Translational Tumorimmunology, Max Delbrück Center, Berlin, Germany., Gudipati V; Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University of Vienna, Vienna, Austria., Reiser J; Fate Therapeutics, San Diego, CA, United States., Mathavan K; Fate Therapeutics, San Diego, CA, United States., Goodrich JP; Fate Therapeutics, San Diego, CA, United States., Huppa JB; Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University of Vienna, Vienna, Austria., Krönke J; Department of Hematology, Oncology and Tumorimmunology, Charité-University Medicine Berlin, Berlin, Germany., Valamehr B; Fate Therapeutics, San Diego, CA, United States., Höpken UE; Microenvironmental Regulation in Autoimmunity and Cancer, Max Delbrück Center, Berlin, Germany., Rehm A; Translational Tumorimmunology, Max Delbrück Center, Berlin, Germany.
المصدر: Frontiers in immunology [Front Immunol] 2024 Jun 24; Vol. 15, pp. 1383136. Date of Electronic Publication: 2024 Jun 24 (Print Publication: 2024).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Lausanne : Frontiers Research Foundation]
مواضيع طبية MeSH: Multiple Myeloma*/immunology , Multiple Myeloma*/therapy , Receptors, CXCR4*/metabolism , Receptors, CXCR4*/genetics , B-Cell Maturation Antigen*/immunology , B-Cell Maturation Antigen*/metabolism , B-Cell Maturation Antigen*/genetics , Killer Cells, Natural*/immunology , Killer Cells, Natural*/metabolism , Receptors, Chimeric Antigen*/immunology , Receptors, Chimeric Antigen*/genetics , Receptors, Chimeric Antigen*/metabolism , Immunotherapy, Adoptive*/methods , Chemokine CXCL12*/metabolism, Humans ; Cell Line, Tumor ; Cytotoxicity, Immunologic
مستخلص: Multiple myeloma (MM) is a plasma cell disease with a preferential bone marrow (BM) tropism. Enforced expression of tissue-specific chemokine receptors has been shown to successfully guide adoptively-transferred CAR NK cells towards the malignant milieu in solid cancers, but also to BM-resident AML and MM. For redirection towards BM-associated chemokine CXCL12, we armored BCMA CAR-NK-92 as well as primary NK cells with ectopic expression of either wildtype CXCR4 or a gain-of-function mutant CXCR4 R334X . Our data showed that BCMA CAR-NK-92 and -primary NK cells equipped with CXCR4 gained an improved ability to migrate towards CXCL12 in vitro . Beyond its classical role coordinating chemotaxis, CXCR4 has been shown to participate in T cell co-stimulation, which prompted us to examine the functionality of CXCR4-cotransduced BCMA-CAR NK cells. Ectopic CXCR4 expression enhanced the cytotoxic capacity of BCMA CAR-NK cells, as evidenced by the ability to eliminate BCMA-expressing target cell lines and primary MM cells in vitro and through accelerated cytolytic granule release. We show that CXCR4 co-modification prolonged BCMA CAR surface deposition, augmented ZAP-70 recruitment following CAR-engagement, and accelerated distal signal transduction kinetics. BCMA CAR sensitivity towards antigen was enhanced by virtue of an enhanced ZAP-70 recruitment to the immunological synapse, revealing an increased propensity of CARs to become triggered upon CXCR4 overexpression. Unexpectedly, co-stimulation via CXCR4 occurred in the absence of CXCL12 ligand-stimulation. Collectively, our findings imply that co-modification of CAR-NK cells with tissue-relevant chemokine receptors affect adoptive NK cell therapy beyond improved trafficking and retention within tumor sites.
Competing Interests: AR and UH filed a patent application for the BCMA CAR used in this manuscript PCT/WO2017211900A1. AR and UH receive research funds from Fate Therapeutics San Diego, CA. JR, KM, JG, and BV are employees of Fate Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Moles, Erdlei, Menzel, Massaro, Fiori, Bunse, Schrimpf, Gerlach, Gudipati, Reiser, Mathavan, Goodrich, Huppa, Krönke, Valamehr, Höpken and Rehm.)
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فهرسة مساهمة: Keywords: BCMA; NK cells; adoptive T cell therapy; chemokine receptor CXCR4; chimeric antigen receptor; multiple myeloma
المشرفين على المادة: 0 (Receptors, CXCR4)
0 (B-Cell Maturation Antigen)
0 (CXCR4 protein, human)
0 (Receptors, Chimeric Antigen)
0 (Chemokine CXCL12)
0 (CXCL12 protein, human)
0 (TNFRSF17 protein, human)
تواريخ الأحداث: Date Created: 20240709 Date Completed: 20240709 Latest Revision: 20240710
رمز التحديث: 20240710
مُعرف محوري في PubMed: PMC11228140
DOI: 10.3389/fimmu.2024.1383136
PMID: 38979422
قاعدة البيانات: MEDLINE
الوصف
تدمد:1664-3224
DOI:10.3389/fimmu.2024.1383136