PRMT5 Deficiency Enforces the Transcriptional and Epigenetic Programs of Klrg1+CD8+ Terminal Effector T Cells and Promotes Cancer Development

Zheng, Yingxia; Chen, Zheyi; Zhou, Bingqian; Chen, Shiyu; Liang, Han; Chen, Ningdai; Ma, Yonggang; Xie, Guohua; Yang, Junyao; Nie, Hong; Shen, Lisong

doi:10.4049/jimmunol.2100523

Cited by 9 publications

(17 citation statements)

References 46 publications

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“…As discussed above, modification of vital epigenetic enzymes can reprogram the T cell differentiation status and effector functions, which can be used to potentiate antitumor T cell functions (Tables 1 and 2 ). 65 , 66 , 67 , 68 Although epigenetic profiles affect the activity of transcription factors, accumulating evidence suggests that several transcriptional regulators can also modulate epigenetic profiles. For instance, the transcription factor TOX orchestrates the epigenetic landscape of exhausted T cells.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic engineering for optimal chimeric antigen receptor T cell therapy

Ito

Kagoya

2022

Cancer Science

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Recent advancements in cancer immunotherapy, such as chimeric antigen receptor (CAR)‐engineered T cell therapy and immune checkpoint therapy, have significantly improved the clinical outcomes of patients with several types of cancer. To broaden its applicability further and induce durable therapeutic efficacy, it is imperative to understand how antitumor T cells elicit cytotoxic functions, survive as memory T cells, or are impaired in their effector functions (exhausted) at the molecular level. T cell properties are regulated by their gene expression profiles, which are further controlled by epigenetic architectures, such as DNA methylation and histone modifications. Multiple studies have elucidated specific epigenetic genes associated with T‐cell phenotypic changes. Conversely, exogenous modification of these key epigenetic factors can significantly alter T cell functions by extensively altering the transcription network, which can be applied in cancer immunotherapy by improving T cell persistence or augmenting effector functions. As CAR‐T cell therapy involves a genetic engineering step during the preparation of the infusion products, it would be a feasible strategy to additionally modulate specific epigenetic genes in CAR‐T cells to improve their quality. Here, we review recent studies investigating how individual epigenetic factors play a crucial role in T‐cell biology. We further discuss future directions to integrate these findings for optimal cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Epigenetic engineering for optimal chimeric antigen receptor T cell therapy

Ito

Kagoya

2022

Cancer Science

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“…Western blot was performed according to our previous study [11] with the following specific primary antibodies: Prmt5, symmetric dimethyl arginine motif, and GAPDH (Cell Signaling Technology), all at a dilution of 1:1000, and the IRDye 800CW‐ or Alexa Fluor 680‐conjugated secondary antibody (1:5000; Abcam).…”

Section: Methodsmentioning

confidence: 99%

“…qRT‐PCR was performed according to our previous study [11]. The Il12 a, Ccl22 , Jak3 , Stat5b , Cd74 , Cd19 , Cd79a , Prmt5 , and β‐actin primer sequences are shown in Supplementary information Table S8.…”

Section: Methodsmentioning

confidence: 99%

Prmt5 deficient mouse B cells display RNA processing complexity and slower colorectal tumor progression

Zhou

Chen

et al. 2023

Eur J Immunol

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Protein arginine methyltransferase 5 (Prmt5) is essential for normal B‐cell development; however, the roles of Prmt5 in tumor‐infiltrating B cells in tumor therapy have not been well elucidated. Here, we revealed that CD19‐cre‐Prmt5fl/fl (Prmt5cko) mice showed smaller tumor weights and volumes in the colorectal cancer mouse model; B cells expressed higher levels of Ccl22 and Il12a, which attracted T cells to the tumor site. Furthermore, we used direct RNA sequencing to comprehensively profile RNA processes in Prmt5 deletion B cells to explore underline mechanisms. We found significantly differentially expressed isoforms, mRNA splicing, poly(A) tail lengths, and m6A modification changes between the Prmt5cko and control groups. Cd74 isoform expressions might be regulated by mRNA splicing; the expression of two novel Cd74 isoforms was decreased, while one isoform was elevated in the Prmt5cko group, but the Cd74 gene expression showed no changes. We observed Ccl22, Ighg1, and Il12a expression was significantly increased in the Prmt5cko group, whereas Jak3 and Stat5b expression was decreased. Ccl22 and Ighg1 expression might be associated with poly(A) tail length, Jak3, Stat5b, and Il12a expression might be modulated by m6A modification. Our study demonstrated that Prmt5 regulates B‐cell function through different mechanisms and supported the development of Prmt5‐targeted antitumor treatments.

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“…Furthermore, PRMT5 also acts directly on the host immune cells to maintain cellular physiology and homeostasis, especially on the effector CD8 + T cells. PRMT5 can affect the deposition of H4R3me2s and H3R8me2s at the Blimp1 locus and force the differentiation of transient effector CD8 + T cells, resulting in a substantial loss of CD8 + T cell numbers and function ( 87 ). Inhibition of PRMT5 is a “double-edged sword”, its inhibition causes reduced AKT/mTOR signaling, which impairs glycolysis and increases fatty acid utilization after human CD8 + Tcells’stimulation leading to metabolic reprogramming ( 88 ).…”

Section: Classification and Biological Functions Of Histone Methyltra...mentioning

confidence: 99%

The role of histone methylase and demethylase in antitumor immunity: A new direction for immunotherapy

Zhang

Chen²,

Liu³

et al. 2023

Front. Immunol.

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Epigenetic modifications may alter the proliferation and differentiation of normal cells, leading to malignant transformation. They can also affect normal stimulation, activation, and abnormal function of immune cells in the tissue microenvironment. Histone methylation, coordinated by histone methylase and histone demethylase to stabilize transcription levels in the promoter area, is one of the most common types of epigenetic alteration, which gained increasing interest. It can modify gene transcription through chromatin structure and affect cell fate, at the transcriptome or protein level. According to recent research, histone methylation modification can regulate tumor and immune cells affecting anti-tumor immune response. Consequently, it is critical to have a thorough grasp of the role of methylation function in cancer treatment. In this review, we discussed recent data on the mechanisms of histone methylation on factors associated with immune resistance of tumor cells and regulation of immune cell function.

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PRMT5 Deficiency Enforces the Transcriptional and Epigenetic Programs of Klrg1+CD8+ Terminal Effector T Cells and Promotes Cancer Development

Abstract: The single-cell RNA-sequencing, bulk RNA-sequencing, and chromatin immunoprecipitation sequencing data presented in this article have been submitted to the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo/query/acc. cgi?acc=GSE186863) under accession number GSE186863.

Cited by 9 publications

References 46 publications

Epigenetic engineering for optimal chimeric antigen receptor T cell therapy

Epigenetic engineering for optimal chimeric antigen receptor T cell therapy

Prmt5 deficient mouse B cells display RNA processing complexity and slower colorectal tumor progression

The role of histone methylase and demethylase in antitumor immunity: A new direction for immunotherapy

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