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Targeting the orphan nuclear receptor NR2F6 in T cells primes tumors for immune checkpoint therapy
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Targeting the orphan nuclear receptor NR2F6 in T cells primes tumors for immune checkpoint therapy
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Journal Article
Targeting the orphan nuclear receptor NR2F6 in T cells primes tumors for immune checkpoint therapy
2020
Overview
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
Nr2f6
CRISPR/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
Nr2f6
CRISPR/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.
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Video abstract.
Graphical abstract
Publisher
BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
Subject
/ Analysis
/ Animals
/ B cells
/ Biomedical and Life Sciences
/ Cancer
/ Cloning
/ Combinatorial treatment regimens
/ CRISPR
/ CRISPR-Cas Systems - genetics
/ CRISPR/Cas9 genetically modified cell therapy
/ Cytokines and Growth Factors
/ DNA
/ Genetically modified organisms
/ Immune Checkpoint Inhibitors - pharmacology
/ Immune Checkpoint Inhibitors - therapeutic use
/ Immune checkpoint NR2F6; transcriptional repressor of CD3+ effector T cell functions
/ Melanoma
/ Methods
/ Mice
/ Programmed Cell Death 1 Receptor - metabolism
/ Repressor Proteins - deficiency
/ Repressor Proteins - metabolism
/ RNA, Guide, CRISPR-Cas Systems - metabolism
/ T cells
/ T-Lymphocytes - drug effects
/ Tumors
