{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:33:33Z","timestamp":1792100013498,"version":"4.4.0"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T00:00:00Z","timestamp":1707264000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T00:00:00Z","timestamp":1707264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Loss of inflammatory effector function, such as cytokine production and proliferation, is a fundamental driver of failure in T cell therapies against solid tumors. Here, we used CRISPR\/Cas9 to genetically disrupt ZFP36, an RNA binding protein that regulates the stability of mRNAs involved in T cell inflammatory function, such as the cytokines IL2 and IFN\u03b3, in human T cells engineered with a clinical-stage mesothelin-targeting CAR to determine whether its disruption could enhance antitumor responses. ZFP36 disruption slightly increased antigen-independent activation and cytokine responses but did not enhance overall performance in vitro or in vivo in a xenograft tumor model with NSG mice. While ZFP36 disruption does not reduce the function of CAR-T cells, these results suggest that singular disruption of ZFP36 is not sufficient to improve their function and may benefit from a multiplexed approach.<\/jats:p>","DOI":"10.1038\/s41598-024-53769-8","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T09:02:23Z","timestamp":1707296543000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["ZFP36 disruption is insufficient to enhance the function of mesothelin-targeting human CAR-T cells"],"prefix":"10.1038","volume":"14","author":[{"given":"David","family":"Mai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tifara","family":"Boyce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aakash","family":"Mehta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"Reff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Scholler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil C.","family":"Sheppard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl H.","family":"June","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,7]]},"reference":[{"key":"53769_CR1","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.1056\/NEJMoa1215134","volume":"368","author":"SA Grupp","year":"2013","unstructured":"Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509\u20131518. https:\/\/doi.org\/10.1056\/NEJMoa1215134 (2013).","journal-title":"N. Engl. J. Med."},{"key":"53769_CR2","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1056\/NEJMoa1407222","volume":"371","author":"SL Maude","year":"2014","unstructured":"Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507\u20131517. https:\/\/doi.org\/10.1056\/NEJMoa1407222 (2014).","journal-title":"N. Engl. J. Med."},{"key":"53769_CR3","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1200\/JCO.2014.56.2025","volume":"33","author":"JN Kochenderfer","year":"2015","unstructured":"Kochenderfer, J. N. et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J. Clin. Oncol. 33, 540\u2013549. https:\/\/doi.org\/10.1200\/JCO.2014.56.2025 (2015).","journal-title":"J. Clin. Oncol."},{"key":"53769_CR4","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1056\/NEJMoa2024850","volume":"384","author":"NC Munshi","year":"2021","unstructured":"Munshi, N. C. et al. Idecabtagene Vicleucel in relapsed and refractory multiple myeloma. N. Engl. J. Med. 384, 705\u2013716. https:\/\/doi.org\/10.1056\/NEJMoa2024850 (2021).","journal-title":"N. Engl. J. Med."},{"key":"53769_CR5","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/ni.2035","volume":"12","author":"EJ Wherry","year":"2011","unstructured":"Wherry, E. J. T cell exhaustion. Nat. Immunol. 12, 492\u2013499. https:\/\/doi.org\/10.1038\/ni.2035 (2011).","journal-title":"Nat. Immunol."},{"key":"53769_CR6","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.immuni.2016.07.011","volume":"45","author":"A Schietinger","year":"2016","unstructured":"Schietinger, A. et al. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45, 389\u2013401. https:\/\/doi.org\/10.1016\/j.immuni.2016.07.011 (2016).","journal-title":"Immunity"},{"key":"53769_CR7","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/s41586-019-1821-z","volume":"576","author":"J Wei","year":"2019","unstructured":"Wei, J. et al. Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy. Nature 576, 471\u2013476. https:\/\/doi.org\/10.1038\/s41586-019-1821-z (2019).","journal-title":"Nature"},{"key":"53769_CR8","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110083","volume":"37","author":"H Zhao","year":"2021","unstructured":"Zhao, H. et al. Genome-wide fitness gene identification reveals Roquin as a potent suppressor of CD8 T cell expansion and anti-tumor immunity. Cell Rep. 37, 110083. https:\/\/doi.org\/10.1016\/j.celrep.2021.110083 (2021).","journal-title":"Cell Rep."},{"key":"53769_CR9","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1182\/blood.2020009309","volume":"138","author":"W Zheng","year":"2021","unstructured":"Zheng, W. et al. Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL. Blood 138, 122\u2013135. https:\/\/doi.org\/10.1182\/blood.2020009309 (2021).","journal-title":"Blood"},{"key":"53769_CR10","doi-asserted-by":"publisher","first-page":"1563","DOI":"10.1038\/s41590-021-01064-3","volume":"22","author":"G Behrens","year":"2021","unstructured":"Behrens, G. et al. Disrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses. Nat. Immunol. 22, 1563\u20131576. https:\/\/doi.org\/10.1038\/s41590-021-01064-3 (2021).","journal-title":"Nat. Immunol."},{"key":"53769_CR11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2218632120","volume":"120","author":"D Mai","year":"2023","unstructured":"Mai, D. et al. Combined disruption of T cell inflammatory regulators Regnase-1 and Roquin-1 enhances antitumor activity of engineered human T cells. Proc. Natl. Acad. Sci. USA 120, e2218632120. https:\/\/doi.org\/10.1073\/pnas.2218632120 (2023).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"53769_CR12","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1038\/nature06253","volume":"450","author":"D Yu","year":"2007","unstructured":"Yu, D. et al. Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450, 299\u2013303. https:\/\/doi.org\/10.1038\/nature06253 (2007).","journal-title":"Nature"},{"key":"53769_CR13","doi-asserted-by":"publisher","first-page":"4779","DOI":"10.1038\/s41467-019-12704-6","volume":"10","author":"SJ Tavernier","year":"2019","unstructured":"Tavernier, S. J. et al. A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation. Nat. Commun. 10, 4779. https:\/\/doi.org\/10.1038\/s41467-019-12704-6 (2019).","journal-title":"Nat. Commun."},{"key":"53769_CR14","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1038\/nature07924","volume":"458","author":"K Matsushita","year":"2009","unstructured":"Matsushita, K. et al. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature 458, 1185\u20131190. https:\/\/doi.org\/10.1038\/nature07924 (2009).","journal-title":"Nature"},{"key":"53769_CR15","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.33057","author":"MJ Moore","year":"2018","unstructured":"Moore, M. J. et al. ZFP36 RNA-binding proteins restrain T cell activation and anti-viral immunity. eLife https:\/\/doi.org\/10.7554\/eLife.33057 (2018).","journal-title":"eLife"},{"key":"53769_CR16","doi-asserted-by":"publisher","first-page":"eabo0981","DOI":"10.1126\/sciimmunol.abo0981","volume":"7","author":"ME Cook","year":"2022","unstructured":"Cook, M. E. et al. The ZFP36 family of RNA binding proteins regulates homeostatic and autoreactive T cell responses. Sci. Immunol. 7, eabo0981. https:\/\/doi.org\/10.1126\/sciimmunol.abo0981 (2022).","journal-title":"Sci. Immunol."},{"key":"53769_CR17","doi-asserted-by":"publisher","first-page":"2274","DOI":"10.1038\/s41467-022-29979-x","volume":"13","author":"G Petkau","year":"2022","unstructured":"Petkau, G. et al. The timing of differentiation and potency of CD8 effector function is set by RNA binding proteins. Nat. Commun. 13, 2274. https:\/\/doi.org\/10.1038\/s41467-022-29979-x (2022).","journal-title":"Nat. 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Roquin binds inducible costimulator mRNA and effectors of mRNA decay to induce microRNA-independent post-transcriptional repression. Nat. Immunol. 11, 725\u2013733. https:\/\/doi.org\/10.1038\/ni.1902 (2010).","journal-title":"Nat. Immunol."},{"key":"53769_CR21","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.immuni.2012.12.004","volume":"38","author":"KU Vogel","year":"2013","unstructured":"Vogel, K. U. et al. Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator mRNAs and control follicular helper T cell differentiation. Immunity 38, 655\u2013668. https:\/\/doi.org\/10.1016\/j.immuni.2012.12.004 (2013).","journal-title":"Immunity"},{"key":"53769_CR22","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1126\/science.281.5379.1001","volume":"281","author":"E Carballo","year":"1998","unstructured":"Carballo, E., Lai, W. S. & Blackshear, P. J. Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science 281, 1001\u20131005. https:\/\/doi.org\/10.1126\/science.281.5379.1001 (1998).","journal-title":"Science"},{"key":"53769_CR23","doi-asserted-by":"publisher","first-page":"47958","DOI":"10.1074\/jbc.M109511200","volume":"276","author":"A Raghavan","year":"2001","unstructured":"Raghavan, A. et al. HuA and tristetraprolin are induced following T cell activation and display distinct but overlapping RNA binding specificities. J. Biol. Chem. 276, 47958\u201347965. https:\/\/doi.org\/10.1074\/jbc.M109511200 (2001).","journal-title":"J. Biol. Chem."},{"key":"53769_CR24","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1042\/bst0300945","volume":"30","author":"PJ Blackshear","year":"2002","unstructured":"Blackshear, P. J. Tristetraprolin and other CCCH tandem zinc-finger proteins in the regulation of mRNA turnover. Biochem. Soc. Trans. 30, 945\u2013952. https:\/\/doi.org\/10.1042\/bst0300945 (2002).","journal-title":"Biochem. Soc. 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Production, concentration and titration of pseudotyped HIV-1-based lentiviral vectors. Nat. Protoc. 4, 495\u2013505. https:\/\/doi.org\/10.1038\/nprot.2009.22 (2009).","journal-title":"Nat. Protoc."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53769-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53769-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53769-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T09:04:43Z","timestamp":1707296683000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-53769-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,7]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["53769"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-53769-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,7]]},"assertion":[{"value":"28 April 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"N.C.S. is a scientific co-founder and holds equity in Bluewhale Bio, is a scientific advisor for Tome Biosciences and Pan Cancer T, and holds equity in Tmunity Therapeutics, and Pfizer Inc. C.H.J. is a scientific co-founder and holds equity in Capstan Therapeutics, Dispatch Biotherapeutics and Bluewhale Bio. C.H.J. serves on the board of AC Immune and is a scientific advisor to BluesphereBio, Cabaletta, Carisma, Cartography, Cellares, Cellcarta, Celldex, Danaher, Decheng, ImmuneSensor, Kite, Poseida, Verismo, Viracta, and WIRB-Copernicus group. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3113"}}