c-Jun overexpression in CAR T cells induces exhaustion resistance

Lynn, Rachel C.; Weber, Evan W.; Sotillo, Elena; Gennert, David; Xu, Peng; Good, Zinaida; Anbunathan, Hima; Lattin, John; Jones, Robert C.; Tieu, Victor; Nagaraja, Surya; Granja, Jeffrey M.; Bourcy, Charles F. A. de; Majzner, Robbie G.; Satpathy, Ansuman T.; Quake, Stephen R.; Monje, Michelle; Chang, Howard Y.; Mackall, Crystal L.

doi:10.1038/s41586-019-1805-z

Cited by 560 publications

(564 citation statements)

References 61 publications

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“…Furthermore, we identified the role of SOCS1 in inducing T cell tolerance in vitro . The methodologies developed here might have important implications for addressing immunological profiles, such as those of dendritic cells and B cells, in other contexts of tolerance induction (Lynn et al, 2019; Nemazee, 2017) as well as in cellular therapy.…”

Section: Discussionmentioning

confidence: 99%

“…In mouse models, deletion of NR4A1, Blimp-1, Cbl-b, NFAT, TSC1, GRAIL, or Egr-2 impairs induction of T cell tolerance in vivo (Haymaker et al, 2017; Jeon et al, 2004; Liu et al, 2019; Macian et al, 2002; Martins et al, 2008; Xie et al, 2012; Zheng et al, 2012). Overexpression of c-Jun in T cells renders them resistant to exhaustion (Lynn et al, 2019). In tolerant human CD4 + and CD8 + T cells, we observed increases in NFAT1, Blimp-1, and NFKBIA as well as a decrease in Jun, AP-1, and Fos (Soto-Nieves et al, 2009), suggesting an association of these genes and TFs with immune tolerance.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies on the induction of T cell tolerance have mainly focused on single genes or transcription factors (TFs), such as Egr-2, nuclear factor of activated T cells (NFAT), and Jun (Lynn et al, 2019; Safford et al, 2005; Soto-Nieves et al, 2009). Recent advances in genome sequencing technologies, including Hi-C (Genome-wide chromosome conformation capture), assays for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA-seq, have enabled gene expression and epigenetic measurements and have revealed variability in immune-cell development and aging (Calderon et al, 2019; Miraldi et al, 2019; Philip et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Three-dimensional genome structure and chromatin accessibility reorganization duringin vivoinduction of human T cell tolerance

Guo

Hou

et al. 2020

Preprint

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Achieving T cell tolerance is a pivotal goal for the field of transplantation and autoimmune diseases. Here, we characterized the gene expression profiles, 3D genome architecture and chromatin accessibility in human steady-state and tolerant T cells, which had been induced in healthy donors by granulocyte-colony-stimulating factor in vivo. We provided the first high-resolution 3D genomic landscape of human tolerant T cells in vivo and identified highly expressed suppressor of cytokine signaling 1 (SOCS1), which is essential for maintaining T cell tolerance and was validated by ex vivo experiments. Mechanistically, SOCS1 is activated by STAT3, which mediates a new interaction between the SOCS1 locus and downstream super-enhancers and is accompanied by the disruption of the CTCF loop between the SOCS1 locus and upstream heterochromatin. This competitive regulation pattern between STAT3 and CTCF is present in the whole genome.Our study defines a regulatory model of transcription factors and provides insight into the induction of immune tolerance.3

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Three-dimensional genome structure and chromatin accessibility reorganization duringin vivoinduction of human T cell tolerance

Guo

Hou

et al. 2020

Preprint

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“…Although not all the predicted core promoter elements might be functional in primary T cells, the high number of the core elements can correlate with the strength of the promoter (25). In addition EF-1 and CMV predominantly enriched for TFs specific or highly expressed in T cells (26–28, 30, 31) such as GATA3, NFATc3, NF-kB, AP1 and c-Jun (Fig. 1e), The number of transcription factor and core promoter element sites predicted within the promoters may provide some explanation for the ability of the CMV and EF-1 promoters to direct long mRNA expression (Fig.…”

Section: Discussionmentioning

confidence: 99%

Promoter Choice: Who Should Drive the CAR in T Cells?

Rad

Poudel

Tan

et al. 2020

Preprint

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Chimeric antigen receptor (CAR) T cell therapy is an effective treatment for B cell malignancies, with emerging potential for the treatment of other hematologic cancers and solid tumors. The strength of the promoter within the CAR cassette will alter CAR-polypeptide levels on the cell surface of the T cell – impacting on the kinetics of activation, survival and memory cell formation in T cells. In addition to the CAR, promoters can be used to drive other genes of interest to enhance CAR T cell function. Expressing multiple genes from a single RNA transcript can be effectively achieved by linking the genes via a ribosomal skip site. However, promoters may differ in their ability to transcribe longer RNAs, or could interfere with lentiviral production, or transduction frequencies. In this study we compared the ability of the strong well-characterized promoters CMV, EF-1, hPGK and RPBSA to drive functional expression of a single RNA encoding three products: GFP, CAR, plus an additional cell-survival gene, Mcl-1. Although the four promoters produced similarly high lentiviral titres, EF-1 gave the best transduction efficacy of primary T cells. Major differences were found in the ability of the promoters to drive expression of long RNA encoding GFP, CAR and Mcl-1, highlighting promoter choice as an important consideration for gene therapy applications requiring the expression of long and complex mRNA.

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“…This progenitor subset retains some proliferative capacity, expresses the transcription factor TCF-1 and can be found in both mice (He et al, 2016;Im et al, 2016;Miller et al, 2019;Utzschneider et al, 2016;Wu et al, 2016) and humans Sade-Feldman et al, 2018). For cellular therapies, there is evidence that therapeutic failures are associated with the development of exhaustion (Chen et al, 2019a;Fraietta et al, 2018) and approaches that antagonize exhaustion are actively being investigated for CAR T cells (Long et al, 2015;Lynn et al, 2019;Wei et al, 2019). Moreover, cellular therapy products that are more stem T MEM -like have improved efficacy (Alizadeh et al, 2019;Sommermeyer et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

In vivoCRISPR screening identifies Fli1 as a transcriptional safeguard that restrains effector CD8 T cell differentiation during infection and cancer

Chen

Arai

Khan

et al. 2020

Preprint

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Improving effector activity of antigen specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (T EFF )-driving transcription factors (TF), the transcriptional coordination of T EFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a novel mechanism restraining T EFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced T EFF responses without compromising memory or exhaustion precursors. Fli1 restrained T EFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs allowing more efficient Runx3-driven T EFF biology. CD8 T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8 T cell transcriptional landscape from excessive ETS:RUNX-driven T EFF cell differentiation. Moreover, genetic deletion of Fli1 improves T EFF differentiation and protective immunity in infections and cancer. Utzschneider et al., 2016; Wu et al., 2016; Zhou et al., 2010) TCF-1 represses (directly or indirectly) T EFF -driving TF such as T-bet and Blimp-1(Tiemessen et al., 2014), and may also have a role in enabling epigenetic changes (Xing et al., 2016). Moreover, a second HMG TF, Tox, is essential for the development of the T EX cell fate by promoting T EX differentiation and repressing of the T EFF lineage differentiation(Alfei et al., 2019; Khan et al., 2019; Scott et al., 2019; Seo et al., 2019; Yao et al., 2019). Tox reprograms the open chromatin landscape, inducing global T EX -specific epigenetic changes and repressing chromatin accessibility associated with T EFF differentiation, in part by recruiting epigenetic modifiers including the lysine acetyltransferase Kat7 (Khan et al., 2019). Despite this work, mechanisms that safeguard against commitment to T EFF differentiation remain poorly understood. Such information could be of considerable utility for immunotherapies focused on enhancing anti-tumor or antiviral activity. However, whereas inactivating pathways like TCF-1 or Tox that would de-repress the entire program of T EFF differentiation are of interest, such approaches result in terminal T EFF and may have limited therapeutic benefit because such cells cannot sustain durable responses. Thus, the discovery of mechanisms that selectively de-repress key aspects of T EFF differentiation, particularly those involved in control of numerical expansion and/or protective immunity would be of considerable interest.Here, we used in vivo CRISPR-Cas9 screening in antigen-specific CD8 T cells responding to acute or chronic viral infection to identify key regulators of T EFF and T EX . In particular, we were interested in identifying genes that resulted by gain-of-function, improving T EFF differentiation (i.e. an "Up" screen (Kaelin, 2017)). The CRISPR-Cas9 system has been used to interrogate the cancer-imm...

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c-Jun overexpression in CAR T cells induces exhaustion resistance

Cited by 560 publications

References 61 publications

Three-dimensional genome structure and chromatin accessibility reorganization duringin vivoinduction of human T cell tolerance

Three-dimensional genome structure and chromatin accessibility reorganization duringin vivoinduction of human T cell tolerance

Promoter Choice: Who Should Drive the CAR in T Cells?

In vivoCRISPR screening identifies Fli1 as a transcriptional safeguard that restrains effector CD8 T cell differentiation during infection and cancer

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