cBAF complex components and MYC cooperate early in CD8+ T cell fate

Guo, Ao; Huang, Hongling; Zhu, Zhexin; Chen, Jinan; Shi, Hao; Yuan, Sujing; Sharma, Piyush; Connelly, Jon P.; Liedmann, Swantje; Dhungana, Yogesh; Li, Zhenrui; Haydar, Dalia; Yang, Mei; Beere, Helen M.; Yustein, Jason T.; DeRenzo, Christopher; Pruett-Miller, Shondra M.; Crawford, Jeremy Chase; Krenciute, Giedre; Roberts, Charles W.M.; Chi, Hongbo; Green, Douglas R.

doi:10.1038/s41586-022-04849-0

Cited by 91 publications

(61 citation statements)

References 71 publications

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“…Further, it has been reported that the IS-proximal daughter cell - interacting with the APC - inherits molecules or organelles related to an effector fate, such as Tbet and CD25, whereas the IS-distal daughter cell inherits components promoting memory fate, such as the proteasome and PKCζ [10], [11], [13]–[21]. Previous studies have demonstrated a remarkable impact of differential expression of fate-determining markers on future fate of first daughter cells by using bulk sorting of cells either expressing the marker of interest at a high or low level after the first cell division upon activation, followed by downstream analyses investigating their future fate [20]–[23]. Furthermore, the role of ACD in fate diversification is supported by the reported transcriptional heterogeneity within CD8 T cells that have undergone one cell division after activation [22], [24].…”

Section: Introductionmentioning

confidence: 99%

Asymmetric cell division safeguards memory CD8 T cell development

Gräbnitz

Stark

Shlesinger

et al. 2022

Preprint

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The strength of T cell receptor (TCR) stimulation and asymmetric distribution of fate determinants are both implied to affect T cell differentiation. Here, we uncovered asymmetric cell division (ACD) as a safeguard mechanism for memory CD8 T cell generation specifically upon strong TCR stimulation. Using live imaging approaches, we found that strong TCR stimulation induced elevated ACD rates and subsequent single cell derived colonies comprised both effector and memory precursor cells. The abundance of memory precursor cells emerging from a single activated T cell positively correlated with first mitosis ACD. Accordingly, preventing ACD by inhibition of PKCzeta during the first mitosis upon strong TCR stimulation markedly curtailed the formation of memory precursor cells. Conversely, no effect of ACD on fate commitment was observed upon weak TCR stimulation. Our data provide new mechanistic insights into the role of ACD for CD8 T cell fate regulation upon different activation conditions.

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Section: Introductionmentioning

confidence: 99%

Asymmetric cell division safeguards memory CD8 T cell development

Gräbnitz

Stark

Shlesinger

et al. 2022

Preprint

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“…The interactions between c-Myc and the epigenetic regulator canonical BRG1/BRM-associated factor (cBAF) promote the remodelling of the chromosomal landscape and the accessibility of T cell differentiation-related gene regions, thereby driving the differentiation of T cells towards effector T cells. Treatment with BRD-K98645985 (BD98), a probable BAF inhibitor, maintained the memory-like phenotype of T cells in vivo and enhanced the antitumor function and persistence of CAR T cells in osteosarcoma and glioma models (139). In summary, epigenetic modifications are promising strategies to address resistance from the perspectives of both CAR T cells and tumour cells.…”

Section: Epigenetic Modulatorsmentioning

confidence: 99%

Combination strategies to optimize the efficacy of chimeric antigen receptor T cell therapy in haematological malignancies

et al. 2022

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Chimeric antigen receptor (CAR) T cell therapy has revolutionized the therapeutic landscape of haematological malignancies. However, resistance and relapse remain prominent limitations, and they are related to the limited persistence and efficacy of CAR T cells, downregulation or loss of tumour antigens, intrinsic resistance of tumours to death signalling, and immune suppressive microenvironment. Rational combined modality treatments are regarded as a promising strategy to further unlock the antitumor potential of CAR T cell therapy, which can be applied before CAR T cell infusion as a conditioning regimen or in ex vivo culture settings as well as concomitant with or after CAR T cell infusion. In this review, we summarize the combinatorial strategies, including chemotherapy, radiotherapy, haematopoietic stem cell transplantation, targeted therapies and other immunotherapies, in an effort to further enhance the effectiveness of this impressive therapy and benefit more patients.

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“…Another famous epigenetic modifier, SWI/SNF complex is related to many cancer types ( 115 ). cBAF is the most canonical sub complex of SWI/SNF and high cBAF activity determines the CD8 + T-cells to effector cells with decrease of memory T-cells ( 116 , 117 ). Thus, cBAF activity deficient CAR T-cells improved therapy response in solid tumor models ( 117 ).…”

Section: Controlling Car T-cell Epigenetics Changesmentioning

confidence: 99%

Enhancing CAR T-cell therapies against solid tumors: Mechanisms and reversion of resistance

Qin

2022

Front. Immunol.

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Chimeric antigen receptor (CAR) T-cell therapy, belonging to adoptive immune cells therapy, utilizes engineered immunoreceptors to enhance tumor-specific killing. By now new generations of CAR T-cell therapies dramatically promote the effectiveness and robustness in leukemia cases. However, only a few CAR T-cell therapies gain FDA approval till now, which are applied to hematologic cancers. Targeting solid tumors through CAR T-cell therapies still faces many problems, such as tumor heterogeneity, antigen loss, infiltration inability and immunosuppressive micro-environment. Recent advances provide new insights about the mechanisms of CAR T-cell therapy resistance and give rise to potential reversal therapies. In this review, we mainly introduce existing barriers when treating solid tumors with CAR T-cells and discuss the methods to overcome these challenges.

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cBAF complex components and MYC cooperate early in CD8+ T cell fate

Cited by 91 publications

References 71 publications

Asymmetric cell division safeguards memory CD8 T cell development

Asymmetric cell division safeguards memory CD8 T cell development

Combination strategies to optimize the efficacy of chimeric antigen receptor T cell therapy in haematological malignancies

Enhancing CAR T-cell therapies against solid tumors: Mechanisms and reversion of resistance

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