Regulatory T cells expressing abundant CTLA‐4 on the cell surface with a proliferative gene profile are key features of human head and neck cancer

Matoba, Takuma; Imai, Masaki; Ohkura, Naganari; Kawakita, Daisuke; Ijichi, Kei; Toyama, Tatsuya; Morita, Akimichi; Murakami, Shingo; Sakaguchi, Shimon; Yamazaki, Sayuri

doi:10.1002/ijc.32024

Cited by 37 publications

(56 citation statements)

References 53 publications

(131 reference statements)

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“…This was done on few samples because of sample limitation and technical difficulty to generate libraries from very few cell numbers. Similarly, CTLA-4 + and CTLA-4 − Tregs from head and neck cancer patients were compared in very small number of samples [21]. We found that the hierarchical clustering of differentially expressed genes showed distinct cluster of TIM-3 + and TIM-3 − T cells ( Figure 3A).…”

Section: Transcriptomic Profile Of Cd4 + Tim-3 + Tils Reveals Their Pmentioning

confidence: 88%

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

et al. 2020

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T cell immunoglobulin mucin-3 (TIM-3) is an immune checkpoint identified as one of the key players in regulating T-cell responses. Studies have shown that TIM-3 is upregulated in the tumor microenvironment (TME). However, the precise role of TIM-3 in colorectal cancer (CRC) TME is yet to be elucidated. We performed phenotypic and molecular characterization of TIM-3+ T cells in the TME and circulation of CRC patients by analyzing tumor tissues (TT, TILs), normal tissues (NT, NILs), and peripheral blood mononuclear cells (PBMC). TIM-3 was upregulated on both CD4+ and CD3+CD4− (CD8+) TILs. CD4+TIM-3+ TILs expressed higher levels of T regulatory cell (Tregs)-signature genes, including FoxP3 and Helios, compared with their TIM-3− counterparts. Transcriptomic and ingenuity pathway analyses showed that TIM-3 potentially activates inflammatory and tumor metastatic pathways. Moreover, NF-κB-mediated transcription factors were upregulated in CD4+TIM-3+ TILs, which could favor proliferation/invasion and induce inflammatory and T-cell exhaustion pathways. In addition, we found that CD4+TIM-3+ TILs potentially support tumor invasion and metastasis, compared with conventional CD4+CD25+ Tregs in the CRC TME. However, functional studies are warranted to support these findings. In conclusion, this study discloses some of the functional pathways of TIM-3+ TILs, which could improve their targeting in more specific therapeutic approaches in CRC patients.

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Section: Transcriptomic Profile Of Cd4 + Tim-3 + Tils Reveals Their Pmentioning

confidence: 88%

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

et al. 2020

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“…In HNSCC the amount of certain immune cell populations and expression levels of various activation and suppressive markers on their cell surface might be altered. Most studies agree that increased Treg infiltration (specifically defined Treg subpopulations expressing various activation markers such as CTLA4, PD-1 or Helios) or increased infiltration of CD4 or CD8 T cells expressing PD-1 is a negative prognostic marker [40,41] in HNSCC, while the presence of memory CD103+ T cells or Tbet+ Tregs correlate with a better prognosis [42,43]. Circulating Treg cells were correlated with negative clinicopathological findings and worse prognosis [44,45,46], on the other hand increased levels of circulating Th17 cells were considered a good prognostic indicator [47].…”

Section: Discussionmentioning

confidence: 99%

Radiotherapy-Induced Changes in the Systemic Immune and Inflammation Parameters of Head and Neck Cancer Patients

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Kis

Badie

et al. 2019

Cancers

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Though radiotherapy is a local therapy, it has systemic effects mainly influencing immune and inflammation processes. This has important consequences in the long-term prognosis and therapy individualization. Our objective was to investigate immune and inflammation-related changes in the peripheral blood of head and neck cancer patients treated with radiotherapy. Peripheral blood cells, plasma and blood cell-derived RNA were isolated from 23 patients before and at two time points after radiotherapy and cellular immune parameters, plasma protein changes and gene expression alterations were studied. Increased regulatory T cells and increased CTLA4 and PD-1 expression on CD4 cells indicated an immune suppression induced by the malignant condition, which was accentuated by radiotherapy. Circulating dendritic cells were strongly elevated before treatment and were not affected by radiotherapy. Decreased endoglin levels in the plasma of patients before treatment were further decreased by radiotherapy. Expression of the FXDR, SESN1, GADD45, DDB2 and MDM2 radiation-response genes were altered in the peripheral blood cells of patients after radiotherapy. All changes were long-lasting, detectable one month after radiotherapy. In conclusion we demonstrated radiotherapy-induced changes in systemic immune parameters of head and neck cancer patients and proposed markers suitable for patient stratification worth investigating in larger patient cohorts.

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“…This could be due to the lower percentage and lower expression level of MDSC subsets in some TT and NT samples. Similarly, CTLA-4 + and CTLA-4 − Tregs from head and neck cancer patients were compared in very small number of samples [56]. The cDNA libraries were generated using QIAseq FX Single Cell RNA Library Kit (Qiagen, Hilden, Germany) following the manufacturer's instructions.…”

Section: Library Preparationmentioning

confidence: 99%

Transcriptomic profiling disclosed the role of DNA methylation and histone modifications in tumor-infiltrating myeloid-derived suppressor cell subsets in colorectal cancer

et al. 2020

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Background: Increased numbers of myeloid-derived suppressor cells (MDSCs) are positively correlated with poor prognosis and reduced survivals of cancer patients. They play central roles in tumor immune evasion and tumor metastasis. However, limited data are available on phenotypic/transcriptomic characteristics of the different MDSCs subsets in cancer. These cells include immature (I-MDSCs), monocytic (M-MDSCs), and polymorphonuclear/ granulocytic (PMN-MDSCs). Methods: Phenotypic characterization of myeloid subsets from 27 colorectal cancer (CRC) patients was assessed by flow cytometric analyses. RNA-sequencing of sorted I-MDSCs, PMN-MDSCs, and antigen-presenting cells (APCs) was also performed. Results: We found that the levels of I-MDSCs and PMN-MDSCs were increased in tumor tissues (TT), compared with normal tissues (NT) in colorectal cancer. Our functional annotation analyses showed that genes associated with histone deacetylase (HDAC) activation-and DNA methylation-mediated transcriptional silencing were upregulated, and histone acetyl transferase (HAT)-related genes were downregulated in tumorinfiltrating I-MDSCs. Moreover, pathways implicated in cell trafficking and immune suppression, including Wnt, interleukin-6 (IL-6), and mitogen-activated protein kinase (MAPK) signaling, were upregulated in I-MDSCs. Notably, PMN-MDSCs showed downregulation in genes related to DNA methylation and HDAC binding. Using an ex vivo model, we found that inhibition of HDAC activation or neutralization of IL-6 in CRC tumor tissues downregulates the expression of genes associated with immunosuppression and myeloid cell chemotaxis, confirming the importance of HDAC activation and IL-6 signaling pathway in MDSC function and chemotaxis. Conclusions: This study provides novel insights into the epigenetic regulations and other molecular pathways in different myeloid cell subsets within the CRC tumor microenvironment (TME), giving opportunities to potential targets for therapeutic benefits.

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Regulatory T cells expressing abundant CTLA‐4 on the cell surface with a proliferative gene profile are key features of human head and neck cancer

Cited by 37 publications

References 53 publications

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

Radiotherapy-Induced Changes in the Systemic Immune and Inflammation Parameters of Head and Neck Cancer Patients

Transcriptomic profiling disclosed the role of DNA methylation and histone modifications in tumor-infiltrating myeloid-derived suppressor cell subsets in colorectal cancer

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