GFI1/HDAC1‐axis differentially regulates immunosuppressive CD73 in human tumor‐associated FOXP3<sup>+</sup>Th17 and inflammation‐linked Th17 cells

Roy, Dia; Bose, Sugata; Pati, Subhadip; Guin, Aharna; Banerjee, Krishnendu; Saha, Sudipto; Singhal, Ayush Keshav; Chakraborty, Jayati; Sarkar, Diptendra Kumar; Sa, Gaurisankar

doi:10.1002/eji.202048892

Cited by 12 publications

(10 citation statements)

References 40 publications

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“…CD24 and ESA positivity or CD4-/CD8- and CD25 negativity were used to assess the purity of those cells flow cytometrically. T cells from healthy volunteers were over-layered on top of primary breast tumor cells (to mimic the TME in vitro ) and cultured for 72 h to generate Tregs ex vivo ( Figure S1 ) ( 38 ).…”

Section: Methodsmentioning

confidence: 99%

FOXP3/HAT1 Axis Controls Treg Infiltration in the Tumor Microenvironment by Inducing CCR4 Expression in Breast Cancer

et al. 2022

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Infiltrating T-regulatory cells in the tumor microenvironment is a key impediment to immunotherapy and is linked to a poor prognosis. We found that tumor-infiltrating Tregs express a higher expression of the chemokine receptor CCR4 than peripheral Tregs in breast cancer patients. CCL22 and CCL17 are released by tumor cells and tumor-associated macrophages, attracting CCR4+ Tregs to the tumor site. The Treg lineage-specific transcription factor FOXP3 changes the CCR4 promoter epigenetically in conjunction with HAT1 to provide a space for FOXP3 binding and activation of the CCR4 gene. To increase CCR4 expression in Tregs, the FOXP3/HAT1 axis is required for permissive (K23 and K27) or repressive (K14 and K18) acetylation of histone-3. In murine breast and melanoma tumor models, genetic ablation of FOXP3 reduced CCR4+ Treg infiltration and tumor size while also restoring anti-tumor immunity. Overexpression of FOXP3, on the other hand, increased CCR4+ Treg infiltration, resulting in a decreased anti-tumor immune response and tumor progression. These findings point to FOXP3 playing a new role in the tumor microenvironment as a transcriptional activator of CCR4 and a regulator of Treg infiltration.

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Section: Methodsmentioning

confidence: 99%

FOXP3/HAT1 Axis Controls Treg Infiltration in the Tumor Microenvironment by Inducing CCR4 Expression in Breast Cancer

et al. 2022

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“…During the typical process of sepsis, the ratio of Th17/Treg cells increases temporarily and then decreases. An abnormal increase in Tregs is accompanied by an inversion of the Th17/Treg ratio, implying the occurrence of immunosuppression [ 138 ]. Patients with septic shock often experience immune collapse, characterized by decreased HLA-DR expression and increased Tregs, especially when culminating in death [ 139 , 140 ].…”

Section: Immune Status Monitoring Of Sepsismentioning

confidence: 99%

Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options

et al. 2022

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Sepsis is a common complication of combat injuries and trauma, and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. It is also one of the significant causes of death and increased health care costs in modern intensive care units. The use of antibiotics, fluid resuscitation, and organ support therapy have limited prognostic impact in patients with sepsis. Although its pathophysiology remains elusive, immunosuppression is now recognized as one of the major causes of septic death. Sepsis-induced immunosuppression is resulted from disruption of immune homeostasis. It is characterized by the release of anti-inflammatory cytokines, abnormal death of immune effector cells, hyperproliferation of immune suppressor cells, and expression of immune checkpoints. By targeting immunosuppression, especially with immune checkpoint inhibitors, preclinical studies have demonstrated the reversal of immunocyte dysfunctions and established host resistance. Here, we comprehensively discuss recent findings on the mechanisms, regulation and biomarkers of sepsis-induced immunosuppression and highlight their implications for developing effective strategies to treat patients with septic shock.

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“…Similarly, CSCs avoid CD8 + cytotoxic T-cell immune surveillance by downregulating MHC-I expression and in turn, impede their growth by selectively augmenting the inhibitory checkpoint receptors ( 23 , 168 ). Additionally, CSCs promote a pro-tumor environment by recruiting immunosuppressive MDSCs and T-regulatory cells, known to release cytokines and bring about metabolic changes that not only help in CSC maintenance but also empower their selective survival over the others ( 14 , 169 , 170 ). The existence and the position of TAMs are observed to be positively correlated with that of CSCs.…”

Section: Cancer Stem Cells and Tamsmentioning

confidence: 99%

Tumor-associated macrophages: an effective player of the tumor microenvironment

Basak,

Sarkar,

Mukherjee

et al. 2023

Front. Immunol.

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Cancer progression is primarily caused by interactions between transformed cells and the components of the tumor microenvironment (TME). TAMs (tumor-associated macrophages) make up the majority of the invading immune components, which are further categorized as anti-tumor M1 and pro-tumor M2 subtypes. While M1 is known to have anti-cancer properties, M2 is recognized to extend a protective role to the tumor. As a result, the tumor manipulates the TME in such a way that it induces macrophage infiltration and M1 to M2 switching bias to secure its survival. This M2-TAM bias in the TME promotes cancer cell proliferation, neoangiogenesis, lymphangiogenesis, epithelial-to-mesenchymal transition, matrix remodeling for metastatic support, and TME manipulation to an immunosuppressive state. TAMs additionally promote the emergence of cancer stem cells (CSCs), which are known for their ability to originate, metastasize, and relapse into tumors. CSCs also help M2-TAM by revealing immune escape and survival strategies during the initiation and relapse phases. This review describes the reasons for immunotherapy failure and, thereby, devises better strategies to impair the tumor–TAM crosstalk. This study will shed light on the understudied TAM-mediated tumor progression and address the much-needed holistic approach to anti-cancer therapy, which encompasses targeting cancer cells, CSCs, and TAMs all at the same time.

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GFI1/HDAC1‐axis differentially regulates immunosuppressive CD73 in human tumor‐associated FOXP3⁺Th17 and inflammation‐linked Th17 cells

Cited by 12 publications

References 40 publications

FOXP3/HAT1 Axis Controls Treg Infiltration in the Tumor Microenvironment by Inducing CCR4 Expression in Breast Cancer

FOXP3/HAT1 Axis Controls Treg Infiltration in the Tumor Microenvironment by Inducing CCR4 Expression in Breast Cancer

Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options

Tumor-associated macrophages: an effective player of the tumor microenvironment

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GFI1/HDAC1‐axis differentially regulates immunosuppressive CD73 in human tumor‐associated FOXP3+Th17 and inflammation‐linked Th17 cells

Cited by 12 publications

References 40 publications

FOXP3/HAT1 Axis Controls Treg Infiltration in the Tumor Microenvironment by Inducing CCR4 Expression in Breast Cancer

FOXP3/HAT1 Axis Controls Treg Infiltration in the Tumor Microenvironment by Inducing CCR4 Expression in Breast Cancer

Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options

Tumor-associated macrophages: an effective player of the tumor microenvironment

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Product

Resources

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GFI1/HDAC1‐axis differentially regulates immunosuppressive CD73 in human tumor‐associated FOXP3⁺Th17 and inflammation‐linked Th17 cells