Overexpression of hypoxia‐inducible factor 1 alpha impacts FoxP3 levels in mycosis fungoides—Cutaneous T‐cell lymphoma: Clinical implications

Alcántara‐Hernández, Marcela; Torres-Zárate, Carmen; Pérez-Montesinos, Gibrán; Cruz, Fermín Jurado-Santa; Domínguez-Gómez, María Antonieta; Peniche-Castellanos, Amelia; Ferat‐Osorio, Eduardo; Neri, Natividad; Nambo, M. Jesús; Alvarado‐Cabrero, Isabel; Moreno-Lafont, Martha; Huerta-Yépez, Sara; Bonifaz, Laura C.

doi:10.1002/ijc.28546

Cited by 13 publications

(12 citation statements)

References 42 publications

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“…Contrasting results regarding modulation of Tregs by HIF‐1α under different pathogenic conditions have been reported. HIF‐1α is overexpressed in cutaneous CD4 + T cell lymphoma, accompanied by a reduction of Foxp3 + cells, and FOXP3 expression is negatively correlated with HIF‐1α expression . Consistent with this finding, inhibition of HIF‐1α by echinomycin decreases Th17 and Th1 allogenic responses and increases the numbers of CD4 + CD25 + Foxp3 + Tregs in spleen and lymph nodes, while also reducing acute graft‐versus‐host disease (GVHD), illustrating that HIF‐1α inhibition increases Tregs differentiation.…”

Section: Hif‐1α and Tregs In Pathogenic Microenvironmentssupporting

confidence: 52%

Hypoxia-inducible factor 1α plays a predominantly negative role in regulatory T cell functions

Hsu

Lai

2018

Journal of Leukocyte Biology

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Hypoxia-inducible factor 1α (HIF-1α) regulates cellular responses to hypoxia. However, conflicting roles for HIF-1α in the functions of regulatory T cells (Tregs) have been reported. In this review, we summarize observations on the requirement for HIF-1α for FOXP3 expression and Tregs development, as well as for HIF-1α-mediated downregulation of FOXP3 and Tregs destabilization. We also examine the association of HIF-1α with Tregs under pathogenic conditions. Based on these findings, we suggest that HIF-1α mainly plays a detrimental role in the function and stability of Tregs and that HIF-1α is disposable for the development and suppressive function of Tregs.

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Section: Hif‐1α and Tregs In Pathogenic Microenvironmentssupporting

confidence: 52%

Hypoxia-inducible factor 1α plays a predominantly negative role in regulatory T cell functions

Hsu

Lai

2018

Journal of Leukocyte Biology

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“…These findings were supported clinically by a recent study in patients with mycosis fungoides, a variant of primary cutaneous T-cell lymphoma, where a negative correlation between HIF1a and Foxp3 expression was established. 81 The role of HIF1a has also been identified in promoting the recruitment of Treg cells to the tumour microenvironment via over-expression of chemokine CCL28 by tumour cells. This promoted tumour tolerance and angiogenesis in human ovarian cancer.…”

Section: Hif and Tumour-infiltrating Lymphocytesmentioning

confidence: 99%

Hypoxia‐inducible factors in regulation of immune responses in tumour microenvironment

2014

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SummaryHypoxia is one of the hallmarks of the tumour microenvironment. It is the result of insufficient blood supply to support proliferating tumour cells. In response to hypoxia, the cellular machinery uses mechanisms whereby the low level of oxygen is sensed and counterbalanced by changing the transcription of numerous genes. Hypoxia-inducible factors (HIF) play a critical role in the regulation of cellular responses to hypoxia. In recent years ample evidence has indicated that HIF play a prominent role in tumour immune responses. Up-regulation of HIF1a promotes immune suppressive activity of myeloid-derived suppressive cells (MDSC) and tumour-associated macrophages (TAM) and rapid differentiation of MDSC to TAM. HIF1a does not affect MDSC differentiation to dendritic cells (DC) but instead causes DC activation. HIF inhibit effector functions of tumour-infiltrating lymphocytes. HIF1a inhibits regulatory T (Treg) cell development by switching the balance towards T helper type 17 cells. However, as a major part of Treg cell differentiation does not take place in the tumour site, a functionally more important role of HIF1a is in the promotion of Treg cell recruitment to the tumour site in response to chemokines. As a result, the presence of Treg cells inside tumours is increased. Hence, HIF play a largely negative role in the regulation of immune responses inside tumours. It appears that therapeutic strategies targeting HIF in the immune system could be beneficial for anti-tumour immune responses.

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“…These immunohistochemical studies also indicate that neoplastic T-cells of MF typically do not express FoxP3 [20,25,30,34,36]. However, in some cases, some neoplastic cells in the epidermis of patch/plaque MF lesions or the dermal infiltrate of tumors express FoxP3 [20,22,35,37]. The level of FoxP3 expression is often weaker than Treg cells [20].…”

Section: Krejsgaard Et Al Recently Reviewed the Complex Relationshipmentioning

confidence: 79%

FoxP3-Positive T-Regulatory Cells in Lymph Nodes with Mycosis Fungoides and Sézary Syndrome

et al. 2014

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Mycosis fungoides and Sézary syndrome are indolent cutaneous T-cell lymphomas, with skin-associated peripheral lymph nodes being the most frequent extracutaneous site of involvement. Acquisition of functional properties of regulatory T-cells by malignant T-cells in advanced disease may contribute to immunosuppression. Whereas previous studies examining FoxP3 protein expression in mycosis fungoides and Sézary syndrome have focused on skin specimens, little data are available on lymph nodes from patients with these conditions. In this study we examined FoxP3+ regulatory T-cells in lymph nodes from 26 patients with mycosis fungoides and Sézary syndrome and correlated the findings with clinical data, molecular assays for T-cell clonality, and flow cytometry. Except for one case of Sézary syndrome in which malignant T-cells expressed FoxP3 protein, a significantly lower number of FoxP3-expressing cells occurred in lymph nodes that were clearly involved with lymphoma as compared to uninvolved nodes. Cox proportional hazards model showed that lymph node rating and histological evidence of transformation, but not number of FoxP3+ cells, were factors significantly associated with adverse prognosis. We speculate that modulation of FoxP3+ cells in lymph nodes involved with lymphoma might play a role in disease progression. Attainment of a regulatory T-cell phenotype by a subset of lymphoma cells might signal a poor prognosis.

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Overexpression of hypoxia‐inducible factor 1 alpha impacts FoxP3 levels in mycosis fungoides—Cutaneous T‐cell lymphoma: Clinical implications

Cited by 13 publications

References 42 publications

Hypoxia-inducible factor 1α plays a predominantly negative role in regulatory T cell functions

Hypoxia-inducible factor 1α plays a predominantly negative role in regulatory T cell functions

Hypoxia‐inducible factors in regulation of immune responses in tumour microenvironment

FoxP3-Positive T-Regulatory Cells in Lymph Nodes with Mycosis Fungoides and Sézary Syndrome

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