Role of regulatory T cells and checkpoint inhibition in hepatocellular carcinoma

Langhans, Bettina; Nischalke, Hans Dieter; Krämer, Benjamin; Dold, Leona; Lutz, Philipp; Mohr, Raphael; Vogt, Annabelle; Toma, Marieta; Eis‐Hübinger, Anna Maria; Nattermann, Jacob; Strassburg, Christian P.; Gonzalez‐Carmona, Maria A.; Spengler, Ulrich

doi:10.1007/s00262-019-02427-4

Cited by 113 publications

(89 citation statements)

References 43 publications

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“…A series of inhibitory membrane proteins on the surface of Tregs can exert their immunosuppressive function through cell-to-cell contact [28]. However, in our experiments, differences in the expression of PD-1 on the surface of Tregs [10,29], were not significantly different between AML and healthy participants, which was consistent with several solid cancers [30][31][32]. Therefore, we inferred that the immunosuppressive function of Tregs in AML patients does not rely on the overexpression of PD-1.…”

Section: Discussionsupporting

confidence: 79%

Hyperfunction of CD4 CD25 regulatory T cells in de novo acute myeloid leukemia

Wan

Zhang

et al. 2020

BMC Cancer

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Background: Acute myeloid leukemia (AML) is a common hematopoietic malignancy that has a high relapse rate, and the number of regulatory T cells (Tregs) in AML patients is significantly increased. The aim of this study was to clarify the role of Tregs in the immune escape of acute myeloid leukemia. Methods: The frequencies of Tregs and the expression of PD-1, CXCR4 and CXCR7 were examined by flow cytometry. The expression of CTLA-4 and GITR was tested by MFI. Chemotaxis assays were performed to evaluate Treg migration. The concentrations of SDF-1α, IFN-γ and TNF-α were examined by ELISA. Coculture and crisscross coculture experiments were performed to examine Treg proliferation and apoptosis and the effect of regulatory B cells (Breg) conversion. Results: The frequencies of Tregs in peripheral blood and bone marrow in AML patients were increased compared with those in healthy participants. AML Tregs had robust migration towards bone marrow due to increased expression of CXCR4. AML Treg-mediated immunosuppression of T cells was achieved through proliferation inhibition, apoptosis promotion and suppression of IFN-γ production in CD4 + CD25 − T cells. AML Bregs induced the conversion of CD4 + CD25 − T cells to Tregs. Conclusion: In AML patients, the Breg conversion effect and robust CXCR4-induced migration led to Treg enrichment in bone marrow. AML Tregs downregulated the function of CD4 + CD25 − T cells, contributing to immune escape.

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Section: Discussionsupporting

confidence: 79%

Hyperfunction of CD4 CD25 regulatory T cells in de novo acute myeloid leukemia

Wan

Zhang

et al. 2020

BMC Cancer

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“…Regulatory T-cells (T-reg) are CD4+/CD25+/FOXP3 +immune-suppressive T-cells whose accumulation in HCC is associated with disease progression [56] and reduced survival [31,57]. They are recruited intratumorally via CCL17/CCL22 secretion by tumour associated macrophages (TAMs) [58,59].…”

Section: Regulatory T-lymphocytesmentioning

confidence: 99%

Immune-based therapies for hepatocellular carcinoma

et al. 2020

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Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related death. The immune-rich contexture of the HCC microenvironment makes this tumour an appealing target for immune-based therapies. Here, we discuss how the functional characteristics of the liver microenvironment can potentially be harnessed for the treatment of HCC. We will review the evidence supporting a therapeutic role for vaccines, cell-based therapies and immune-checkpoint inhibitors and discuss the potential for patient stratification in an attempt to overcome the series of failures that has characterised drug development in this disease area.

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“…Tregs are a subset of CD4 + CD25 + CD127 − T lymphocytes which constitutively express the transcription factor FoxP3 (forkhead box P3). Activated Tregs inhibit different subsets of immune cells via contactdependent ways between checkpoint molecules and their ligands involving PD-1, PD-L1, CTLA-4, GITR, Tim-3, and galectin-9 4 . Tregs have been shown to increase with tumor stage and correlate with poor prognosis in HCC 5,6 .…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Regulatory T cells enhance stem-like characteristics of hepatocellular carcinoma cells through Wnt/β-catenin pathway

Liu

Pan

et al. 2020

Preprint

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Background: Tumor initiating cells (TICs) were confirmed to drive the therapeutic resistance of hepatocellular carcinoma (HCC), but the mechanism by which tumor microenvironment maintains the HCC stemness is not fully understood. This study aims to investigate the effect of regulatory T cells (Tregs) on the TICs characteristics of HCC. Methods: Immunocytochemistry, flow cytometry, real-time PCR, western blot, in vitro sphere-formation, and in vivo tumorigenesis assay were used to detect HCC TIC characteristics. Additionally, the association between FoxP3 expression, Wnt/β-catenin pathway activation, and HCC stemness were analyzed by forced expression or inhibition of FoxP3. Results: It was showed Tregs enhanced the stemness of HCC cells by upregulation of TIC-related markers CD133, Oct3/4, Sox2, c-Myc, Klf4, Nanog, CD13, EpCAM, and induction of epithelial to mesenchymal transition (EMT), increase of TICs ratio, as well as promotion of tumorigenic ability. Moreover, β-catenin and c-Myc were upregulated in HCC cells when co-cultured with Tregs. After Wnt/β-catenin pathway inhibition, HCC stemness was also inhibited. In addition, Tregs-derived exosomes played the same role as Tregs in enhancing HCC TIC properties, and exosome inhibition led to decreased TIC ratio as well as TIC markers expression. Furthermore, Tregs-derived exosomes down-regulate FoxP3 and GSK3β of HCC cells. Forced expression of FoxP3 resulted in increased GSK3β, decreased β-catenin and TIC ratio of HCC. In contrast, FoxP3 interference reduced GSK3β, increased β-catenin and TIC ratio. Conclusions: This study, for the first time, demonstrated Tregs enhanced HCC stemness through Wnt//β-catenin pathway by down-regulating FoxP3.

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Role of regulatory T cells and checkpoint inhibition in hepatocellular carcinoma

Cited by 113 publications

References 43 publications

Hyperfunction of CD4 CD25 regulatory T cells in de novo acute myeloid leukemia

Hyperfunction of CD4 CD25 regulatory T cells in de novo acute myeloid leukemia

Immune-based therapies for hepatocellular carcinoma

WITHDRAWN: Regulatory T cells enhance stem-like characteristics of hepatocellular carcinoma cells through Wnt/β-catenin pathway

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