The Fate of Th17 Cells is Shaped by Epigenetic Modifications and Remodeled by the Tumor Microenvironment

Renaude, Elodie; Kroemer, Marie; Loyon, Romain; Binda, Delphine; Borg, Christophe; Guittaut, Michaël; Hervouet, Éric; Peixoto, Paul

doi:10.3390/ijms21051673

Cited by 28 publications

(30 citation statements)

References 107 publications

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“…It has been estimated that Epstein-Barr virus infection is associated with approximately 200,000 malignancies each year [42], and EBS appears to dysregulate the expression of TCL1-family genes, leading to several typical lymphocyte cancers [43]. Th17 cells are a subset of CD4 + T cells, and high levels of tumor-infiltrating Th17 cells are correlated with lymph node metastases and have a negative impact on the postoperative survival of cancer patients [44].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive profiling of immune-related genes in soft tissue sarcoma patients

Chen

Huang

et al. 2020

J Transl Med

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Background: Immune-related genes (IRGs) have been confirmed to have an important role in tumorigenesis and tumor microenvironment formation. Nevertheless, a systematic analysis of IRGs and their clinical significance in soft tissue sarcoma (STS) patients is lacking. Methods: Gene expression files from The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression (GTEx) were used to select differentially expressed genes (DEGs). Differentially expressed immune-related genes (DEIRGs) were determined by matching the DEG and ImmPort gene sets, which were evaluated by functional enrichment analysis. Unsupervised clustering of the identified DEIRGs was conducted, and associations with prognosis, the tumor microenvironment (TME), immune checkpoints, and immune cells were analyzed simultaneously. Two prognostic signatures, one for overall survival (OS) and one for progression free survival (PFS), were established and validated in an independent set. Finally, two transcription factor (TF)-IRG regulatory networks were constructed, and a crucial regulatory axis was validated. Results: In total, 364 DEIRGs and four clusters were identified. OS, TME scores, five immune checkpoints, and 12 types of immune cells were found to be significantly different among the four clusters. The two prognostic signatures incorporating 20 DEIRGs showed favorable discrimination and were successfully validated. Two nomograms combining signature and clinical variables were generated. The C-indexes were 0.879 (95%CI 0.832 ~ 0.926) and 0.825 (95%CI 0.776 ~ 0.874) for the OS and PFS signatures, respectively. Finally, TF-IRG regulatory networks were established, and the MYH11-ADM regulatory axis was verified in three independent datasets. Conclusion: This comprehensive analysis of the IRG landscape in soft tissue sarcoma revealed novel IRGs related to carcinogenesis and the immune microenvironment. These findings have implications for prognosis and therapeutic responses, which reveal novel potential prognostic biomarkers, promote precision medicine, and provide potential novel targets for immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Comprehensive profiling of immune-related genes in soft tissue sarcoma patients

Chen

Huang

et al. 2020

J Transl Med

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“…IL-6 is a pro-inflammatory cytokine produced by macrophages, T cells, B cells, and intestinal epithelial cells [ 16 ]. Several studies have elucidated the effects of IL-6 on T cell differentiation, which promotes polarization into Th17 through JAK-STAT3 signaling [ 17 , 18 ]. Our results from animal experiments show that the oral administration of THF significantly reduced the mRNA levels of IL-6 in colon tissue ( Figure 6 C) and mRNA levels of RORγt and IL-17 in the MLN ( Figure 7 C,D).…”

Section: Discussionmentioning

confidence: 99%

6,7,4′-Trihydroxyflavanone Protects against Dextran Sulfate Sodium-Induced Colitis by Regulating the Activity of T Cells and Colon Cells In Vivo

Lee

Jeong

2021

IJMS

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Colitis is a multifactorial disorder that mostly occurs in the gastrointestinal tract. Despite improvements in mucosal inflammation research, little is known regarding the small bioactive molecules that are beneficial for regulating T cells and colon cell activity. 6,7,4′-trihydroxyflavanone (THF) is a flavanone that possesses anti-osteoclastogenesis activity and exerts protective effects against methamphetamine-induced immunotoxicity. Whether THF mitigates intestinal inflammation by regulating T cells and colon cell activity remains unknown. In the present study, Jurkat and HT-29 cells were used for in vitro experiments, and dextran sulfate sodium (DSS)-induced colitis model in mice was used for in vivo experiment. We observed that THF did not have a negative effect on the viability of Jurkat and HT-29 cells. Quantitative PCR and Western blot analysis revealed that THF regulates the activity of Jurkat cells and HT-29 cells via the NFκB and MAPK pathways under stimulated conditions. In the DSS-induced colitis model, oral administration of THF attenuated the manifestations of DSS-induced colitis, including a reduction in body weight, shrinkage of the colon, and enhanced expression of pro-inflammatory cytokines in the colon and mesenteric lymph nodes. These data suggest that THF alleviates DSS-induced colitis by modulating the activity of T cells and colon cells in vivo.

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“…Yet, literature suggests that epigenetic remodeling plays a key role in Th17/Th1* cell plasticity and differentiation. 52 Ongoing studies investing on epigenetic modification of Th17 within CRC liver metastases could shed light to better understand their biology in views of remodeling the tumor microenvironment using molecule targeting epigenetic enzymes to reprogram Th17 toward a Th1 phenotype.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the prognostic value of CD4 T cell subsets expanded from tumor-infiltrating lymphocytes of colorectal cancer liver metastases

Kroemer

Turco

Spehner

et al. 2020

J Immunother Cancer

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BackgroundThe positive role of CD8+ tumor-infiltrating lymphocytes (TIL) in patients with colorectal cancer (CRC) has been well described but the prognostic value of CD4 T cell subsets remained to be investigated. In this study, we expanded TIL from surgically resected liver metastases of patients with CRC and characterized the phenotype and the prognostic value of expanded-CD4 T cells.MethodsLiver metastases were surgically resected from 23 patients with CRC. Tumors were enzymatically digested and cultured in high dose of interleukin-2 for up to 5 weeks. T cell phenotype and reactivity of cultured-T cells were measured by flow cytometry and correlated with patients’ clinical outcomes.ResultsWe successfully expanded 21 over 23 TIL from liver metastases of patients with CRC. Interestingly, we distinguished two subsets of expanded T cells based on T cell immunoglobulin mucin domain-containing protein 3 (TIM-3) expression. Medians fold expansion of expanded T cells after rapid expansion protocol was higher in CD3+TIM-3low cultures. In an attempt to investigate the correlation between the phenotype of expanded CD4 T cells and clinical outcomes, we observed on one hand that the level of Tregs in culture as well as the expression of both PD1 and TIM-3 by expanded T cells was not correlated to the clinical outcomes. Interestingly, on the other hand, cultures containing high levels of Th17 cells were associated with a poor prognosis (p=0.0007).ConclusionsOur data confirmed the presence of Th17 cells in expanded T cells from liver metastases. Among CD4 T cell characteristics investigated, TIM-3 but not programmed cell death protein 1 predicted the expansion capacity of TIL while only the Th17 phenotype showed correlation with patients’ survival, suggesting a particular role of this T cell subset in CRC immune contexture.Trial registration numberNCT02817178.

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The Fate of Th17 Cells is Shaped by Epigenetic Modifications and Remodeled by the Tumor Microenvironment

Cited by 28 publications

References 107 publications

Comprehensive profiling of immune-related genes in soft tissue sarcoma patients

Comprehensive profiling of immune-related genes in soft tissue sarcoma patients

6,7,4′-Trihydroxyflavanone Protects against Dextran Sulfate Sodium-Induced Colitis by Regulating the Activity of T Cells and Colon Cells In Vivo

Investigation of the prognostic value of CD4 T cell subsets expanded from tumor-infiltrating lymphocytes of colorectal cancer liver metastases

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