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| Item Type: | Article |
|---|---|
| Title: | CXCR4 has a dual role in improving the efficacy of BCMA redirected CAR-NK cells in multiple myeloma |
| Creators Name: | Moles, M.W., Erdlei, H., Menzel, L., Massaro, M., Fiori, A., Bunse, M., Schrimpf, M., Gerlach, K., Gudipati, V., Reiser, J., Mathavan, K., Goodrich, J., Huppa, J.B., Kroenke, J., Valamehr, B., Höpken, U.E. and Rehm, A. |
| Abstract: | 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. |
| Keywords: | BCMA, Chimeric Antigen Receptor, NK Cells, Multiple Myeloma, Chemokine Receptor, CXCR4, Adoptive T Cell Therapy |
| Source: | Frontiers in Immunology |
| ISSN: | 1664-3224 |
| Publisher: | Frontiers Media SA |
| Volume: | 15 |
| Page Range: | 1383136 |
| Date: | 24 June 2024 |
| Official Publication: | https://doi.org/10.3389/fimmu.2024.1383136 |
| PubMed: | View item in PubMed |
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