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http://purl.uniprot.org/citations/31937317http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/31937317http://www.w3.org/2000/01/rdf-schema#comment"

Background

NR2F6 has been proposed as an alternative cancer immune checkpoint in the effector T cell compartment. However, a realistic assessment of the in vivo therapeutic potential of NR2F6 requires acute depletion.

Methods

Employing primary T cells isolated from Cas9-transgenic mice for electroporation of chemically synthesized sgRNA, we established a CRISPR/Cas9-mediated acute knockout protocol of Nr2f6 in primary mouse T cells.

Results

Analyzing these Nr2f6CRISPR/Cas9 knockout T cells, we reproducibly observed a hyper-reactive effector phenotype upon CD3/CD28 stimulation in vitro, highly reminiscent to Nr2f6-/- T cells. Importantly, CRISPR/Cas9-mediated Nr2f6 ablation prior to adoptive cell therapy (ACT) of autologous polyclonal T cells into wild-type tumor-bearing recipient mice in combination with PD-L1 or CTLA-4 tumor immune checkpoint blockade significantly delayed MC38 tumor progression and induced superior survival, thus further validating a T cell-inhibitory function of NR2F6 during tumor progression.

Conclusions

These findings indicate that Nr2f6CRISPR/Cas9 knockout T cells are comparable to germline Nr2f6-/- T cells, a result providing an independent confirmation of the immune checkpoint function of lymphatic NR2F6. Taken together, CRISPR/Cas9-mediated acute Nr2f6 gene ablation in primary mouse T cells prior to ACT appeared feasible for potentiating established PD-L1 and CTLA-4 blockade therapies, thereby pioneering NR2F6 inhibition as a sensitizing target for augmented tumor regression. Video abstract."xsd:string
http://purl.uniprot.org/citations/31937317http://purl.org/dc/terms/identifier"doi:10.1186/s12964-019-0454-z"xsd:string
http://purl.uniprot.org/citations/31937317http://purl.uniprot.org/core/author"Baier G."xsd:string
http://purl.uniprot.org/citations/31937317http://purl.uniprot.org/core/author"Hermann-Kleiter N."xsd:string
http://purl.uniprot.org/citations/31937317http://purl.uniprot.org/core/author"Klepsch V."xsd:string
http://purl.uniprot.org/citations/31937317http://purl.uniprot.org/core/author"Brigo N."xsd:string
http://purl.uniprot.org/citations/31937317http://purl.uniprot.org/core/author"Humer D."xsd:string
http://purl.uniprot.org/citations/31937317http://purl.uniprot.org/core/author"Pommermayr M."xsd:string
http://purl.uniprot.org/citations/31937317http://purl.uniprot.org/core/date"2020"xsd:gYear
http://purl.uniprot.org/citations/31937317http://purl.uniprot.org/core/name"Cell Commun Signal"xsd:string
http://purl.uniprot.org/citations/31937317http://purl.uniprot.org/core/pages"8"xsd:string
http://purl.uniprot.org/citations/31937317http://purl.uniprot.org/core/title"Targeting the orphan nuclear receptor NR2F6 in T cells primes tumors for immune checkpoint therapy."xsd:string
http://purl.uniprot.org/citations/31937317http://purl.uniprot.org/core/volume"18"xsd:string
http://purl.uniprot.org/citations/31937317http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/31937317
http://purl.uniprot.org/citations/31937317http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/31937317
http://purl.uniprot.org/uniprot/#_P43136-mappedCitation-31937317http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/31937317
http://purl.uniprot.org/uniprot/#_Q3UIT0-mappedCitation-31937317http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/31937317
http://purl.uniprot.org/uniprot/P43136http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/31937317
http://purl.uniprot.org/uniprot/Q3UIT0http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/31937317