IL-7R–Dependent Phosphatidylinositol 3-Kinase Competes with the STAT5 Signal to Modulate T Cell Development and Homeostasis

Cui, Guangwei; Shimba, Akihiro; Ma, Guangyong; Takahara, Kazuhiko; Tani-ichi, Shizue; Zhu, Yuanbo; Asahi, T.; Abe, Akifumi; Miyachi, Hitoshi; Kitano, Satsuki; Hara, Takahiro; Yasunaga, Jun Ichirou; Suwanai, Hirotsugu; Yamada, Hisakata; Matsuoka, Masao; Ueki, Kohjiro; Yoshikai, Yasunobu; Ikuta, Koichi

doi:10.4049/jimmunol.1900456

Cited by 12 publications

(7 citation statements)

References 42 publications

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“…Therefore, highlighting a key pathway in immune response that is epigenetically suppressed in ex vivo human GBM samples may serve more efficient development of biological therapies in the future. IL-7 has been identified as a key cytokine in the compensatory reaction to declining lymphocytes [ 28 , 29 ]. While exogenous administration of IL-7 could elevate the CD4+ and CD8+ T-cell counts, higher doses of this cytokine are associated with significant toxicity [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Suppression of the IL-7 Pathway in Progressive Glioblastoma

et al. 2022

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Background: Immune evasion in glioblastoma (GBM) shields cancer cells from cytotoxic immune response. Methods: We investigated CpG methylation in promoters, genes, and pathways in 22 pairs of formalin-fixed paraffin-embedded sequential (FFPE) GBM using restricted resolution bisulfite sequencing (RRBS) and bioinformatic analyses. Results: Gene ontology revealed hypermethylation in elements of the innate and adaptive immune system when recurrent GBM samples (GBMrec) were compared to control (CG) and primary GBM samples (GBMprim). Higher methylation levels of the IL-7 signaling pathway and response to IL-7 were found in GBMrec suggesting a progressive blockade of the IL-7 driven T cell response in sequential GBM. Analyses of the Cancer Genome Atlas array-based data confirmed hypermethylation of the IL-7 pathway in recurrent compared with primary GBM. We also quantified DNA CpG methylation in promoter and gene regions of the IL-7 ligand and IL-7 α-receptor subunit in individual samples of a large RRBS-based sequential cohort of GBM in a Viennese database and found significantly higher methylation levels in the IL-7 receptor α-subunit in GBMrec compared with GBMprim. Conclusions: This study revealed the progressive suppression of the IL-7 receptor-mediated pathway as a means of immune evasion by GBM and thereby highlighted it as a new treatment target.

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Section: Discussionmentioning

confidence: 99%

Epigenetic Suppression of the IL-7 Pathway in Progressive Glioblastoma

et al. 2022

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“…IL-7 receptor complex could activate PI3K/Akt/mTOR signaling pathway in lung cancer cell line and leukemia transformation cell line [ 34 , 35 ]. IL-7 receptor-dependent PI3K also competed with STAT5 signal to regulate T cell development and homeostasis in mice [ 36 ]. Taken together, IL-7 induced an increase in sCD27 mRNA variant in CD8 + T cells and release of sCD127 by CD8 + T cells probably through PI3K signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-7 regulates CD127 expression and promotes CD8+ T cell activity in patients with primary cutaneous melanoma

Qiao

Guo

et al. 2022

BMC Immunol

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Background Interleukin (IL)-7 signaling through CD127 is impaired in lymphocytes in cancers and chronic infections, resulting in CD8+ T cell exhaustion. The mechanisms underlying CD8+ T cell responses to IL-7 in melanoma remain not completely elucidated. We previously showed reduced IL-7 level in melanoma patients. Thus, the aim of this study was to investigate the effect of IL-7 regulation on CD127 expression and CD8+ T cell responses in melanoma. Methods Healthy controls and primary cutaneous melanoma patients were enrolled. Membrane-bound CD127 (mCD127) expression on CD8+ T cells was determined by flow cytometry. Soluble CD127 (sCD127) protein level was measured by ELISA. Total CD127 and sCD127 mRNA level was measured by real-time PCR. CD8+ T cells were stimulated with recombinant human IL-7, along with signaling pathway inhibitors. CD8+ T cells were co-cultured with melanoma cell line, and the cytotoxicity of CD8+ T cells was assessed by measurement of lactate dehydrogenase expression. Results Plasma sCD127 was lower in melanoma patients compared with controls. The percentage of CD8+ T cells expressing mCD127 was higher, while sCD127 mRNA level was lower in peripheral and tumor-infiltrating CD8+ T cells from melanoma patients. There was no significant difference of total CD127 mRNA expression in CD8+ T cells between groups. IL-7 stimulation enhanced total CD127 and sCD127 mRNA expression and sCD127 release by CD8+ T cells. However, mCD127 mRNA expression on CD8+ T cells was not affected. This process was mainly mediated by phosphatidylinositol 3-kinase (PI3K) pathway. CD8+ T cells from melanoma patients exhibited decreased cytotoxicity. IL-7 stimulation promoted CD8+ T cell cytotoxicity, while inhibition of PI3K dampened IL-7-induced elevation of CD8+ T cell cytotoxicity. Conclusion The current data suggested that insufficient IL-7 secretion might contribute to CD8+ T cell exhaustion and CD127 dysregulation in patients with primary cutaneous melanoma.

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“…It is suggested that the increased expression of LDHA in the most invasive subgroup of the hypoxia group activates the PI3K pathway, which promotes the invasion and metastasis of pancreatic cancer by regulating the differentiation, proliferation, metabolism, and stress of pancreatic cancer cells under hypoxic conditions (Supplementary Figure S7). PI3K inhibitors can inhibit the LDHA-induced activation of the PI3K signaling pathway 52,53 , which may become a new candidate drug for the treatment of pancreatic cancer. The efficacy of PI3K inhibitors in pancreatic cancer will be further verified in subsequent experiments.…”

Section: Discussionmentioning

confidence: 99%

Hypoxic microenvironment induced spatial transcriptome changes in pancreatic cancer

et al. 2021

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Objective: Hypoxia is a significant feature of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). It is associated with tumor invasion, metastasis, and drug resistance. However, the spatial distribution of hypoxia-related heterogeneity in PDAC remains unclear. Methods: Spatial transcriptomics (STs), a new technique, was used to investigate the ST features of engrafted human PDAC in the ischemic hind limbs of nude mice. Transcriptomes from ST spots in the hypoxic tumor and the control were clustered using differentially-expressed genes. These data were compared to determine the spatial organization of hypoxia-induced heterogeneity in PDAC. Clinical relevance was validated using the Tumor Cancer Genome Atlas and KM-plotter databases. The CMAP website was used to identify molecules that may serve as therapeutic targets for PDAC. Results: ST showed that the tumor cell subgroups decreased to 7 subgroups in the hypoxia group, compared to 9 subgroups in the control group. Different subgroups showed positional characteristics and different gene signatures. Subgroup 6 located at the invasive front showed a higher proliferative ability under hypoxia. Subgroup 6 had active functions including cell proliferation, invasion, and response to stress. Expressions of hypoxia-related genes, LDHA, TPI1, and ENO1, induced changes. CMAP analysis indicated that ADZ-6482, a PI3K inhibitor, was targeted by the invasive subgroup in hypoxic tumors. Conclusions: This study is the first to describe hypoxic microenvironment-induced spatial transcriptome changes in PDAC, and to identify potential treatment targets for PDAC. These data will provide the basis for further investigations of the prognoses and treatments of hypoxic tumors.

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IL-7R–Dependent Phosphatidylinositol 3-Kinase Competes with the STAT5 Signal to Modulate T Cell Development and Homeostasis

Cited by 12 publications

References 42 publications

Epigenetic Suppression of the IL-7 Pathway in Progressive Glioblastoma

Epigenetic Suppression of the IL-7 Pathway in Progressive Glioblastoma

Interleukin-7 regulates CD127 expression and promotes CD8+ T cell activity in patients with primary cutaneous melanoma

Hypoxic microenvironment induced spatial transcriptome changes in pancreatic cancer

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