{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T03:29:33Z","timestamp":1791948573633,"version":"4.3.4"},"reference-count":55,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wilhelm-Sander-Stiftung","award":["2202.046.1"],"award-info":[{"award-number":["2202.046.1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chimeric antigen receptor (CAR) T-cell therapy directed to CD19 and B-cell maturation antigen has revolutionized treatment of B-cell leukemia and lymphoma, and multiple myeloma. However, identifying suitable targets for acute myeloid leukemia (AML) remains challenging due to concurrent expression of potential target antigens on normal hematopoietic stem cells or tissues. As the stress-induced B7H6 molecule is rarely found on normal tissues but expressed on many cancers including AML and melanoma, the NKp30-ligand B7H6 emerges as a promising target for NKp30-based CAR T therapy for these tumors. In this study, we report a comprehensive B7H6 expression analysis on primary AML and melanoma as well as on different tumor cell-lines examined by RT-qPCR and flow cytometry, and efficient anti-tumor reactivity of NKp30-CAR T cells to AML and melanoma. To overcome limitations of autologous CAR T-cell fitness-dependent efficacy and patient-tailored production, we generated CRISPR\/Cas9-mediated TCR-knockout (TCRKO) NKp30-CAR T cells as an off-the-shelf approach for CAR T therapy. Functional studies comparing NKp30-CD28 CAR or NKp30-CD137 CAR TCR+ and TCRKO T lymphocytes revealed superior anti-tumoral immunity of NKp30-CD28 CAR TCRKO T cells to AML and melanoma cell lines in vitro, and effective control of tumor burden in an NSG melanoma-xenograft mouse model. In conclusion, these findings highlight the therapeutic potential of NKp30 CAR TCRKO T cells for adoptive T-cell therapy to B7H6-expressing cancers, including melanoma and AML.<\/jats:p>","DOI":"10.3390\/ijms26178235","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T06:26:31Z","timestamp":1756189591000},"page":"8235","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CRISPR\/Cas9 TCR-Edited NKp30 CAR T Cells Exhibit Superior Anti-Tumor Immunity to B7H6-Expressing Leukemia and Melanoma"],"prefix":"10.3390","volume":"26","author":[{"given":"Sedigheh","family":"Givi","sequence":"first","affiliation":[{"name":"Department of Medicine, Hematology & Medical Oncology, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"},{"name":"Research Center for Immunotherapy, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3362-6546","authenticated-orcid":false,"given":"Benedikt J.","family":"Lohnes","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology & Medical Oncology, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"},{"name":"Research Center for Immunotherapy, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saber","family":"Ebrahimi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology & Medical Oncology, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"},{"name":"Research Center for Immunotherapy, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Riedel","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology & Medical Oncology, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"},{"name":"Research Center for Immunotherapy, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sneha","family":"Khokhali","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology & Medical Oncology, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"},{"name":"Research Center for Immunotherapy, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamsul A.","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology & Medical 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Germany"},{"name":"Research Center for Immunotherapy, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hakim","family":"Echchannaoui","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology & Medical Oncology, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"},{"name":"Research Center for Immunotherapy, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"},{"name":"Partner Site Frankfurt\/Mainz, German Consortium for Translational Cancer Research (DKTK), 55101 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Bockamp","sequence":"additional","affiliation":[{"name":"Research Center for Immunotherapy, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"},{"name":"Institute for Translational Immunology, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya C.","family":"Andre","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology and General Pediatrics, Children\u2019s University Hospital, University of T\u00fcbingen, 72074 T\u00fcbingen, Germany"},{"name":"Department of Pediatric Intensive Care, Children\u2019s University Hospital, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4302-3240","authenticated-orcid":false,"given":"Hinrich","family":"Abken","sequence":"additional","affiliation":[{"name":"Division Genetic Immunotherapy, Leibniz Institute for Immunotherapy, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4270-2209","authenticated-orcid":false,"given":"Matthias","family":"Theobald","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology & Medical Oncology, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"},{"name":"Research Center for Immunotherapy, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"},{"name":"Partner Site Frankfurt\/Mainz, German Consortium for Translational Cancer Research (DKTK), 55101 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6714-6923","authenticated-orcid":false,"given":"Udo F.","family":"Hartwig","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology & Medical Oncology, University Medical Center of Johannes Gutenberg University, 55101 Mainz, Germany"},{"name":"Research Center 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