Yap suppresses T cell function and infiltration in the tumor microenvironment

Stampouloglou, Eleni; Federico, Anthony; Slaby, Emily M.; Monti, Stefano; Szeto, Gregory L.; Varelas, Xaralabos

doi:10.1101/644757

Cited by 8 publications

(16 citation statements)

References 77 publications

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“…In addition, although the C1 group had the highest TCR/BCR Shannon and Richness scores, ESCA patients C1 tended to have a poor prognosis. Most studies showed that the higher diversity of TCR and BCR is linked to a better prognosis of cancer patients [32], which is controversial with our results. A possible explanation is that the immune system in ESCA might construct several fixed immune responses against only a few antigens rather than various responses against lots of different antigens [17].…”

Section: Specific Immune Mechanisms Of the Three Immunology Subtypes ...contrasting

confidence: 92%

Pan‐cancer multi‐omics analyses reveal crosstalk between the Hippo and immune signaling pathways in the tumor microenvironment

et al. 2021

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The Hippo signaling pathway is critical for carcinogenesis. However, the roles of the Hippo signaling pathway in the tumor immune microenvironment have been rarely investigated. This study systematically analyzed the relationship between the Hippo signaling pathway and immune cell infiltration across 32 cancer types. Both bioinformatics analyses and biological experiments revealed that the downstream effector of Hippo signaling YAP1 might inhibit CD8+ T cell infiltration by upregulating the expression of the transcription factor CREB1 in uterine corpus endometrial carcinoma. In addition, esophageal carcinoma (ESCA) patients were classified into three subtypes based on the Hippo-immune gene panel. The subtypes of ESCA had distinct characteristics in immune cell infiltration, immune pathways, and prognosis. Thus, this study also reveals a new classification of the immune subtypes with prognostic characteristics in ESCA.

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Section: Specific Immune Mechanisms Of the Three Immunology Subtypes ...contrasting

confidence: 92%

Pan‐cancer multi‐omics analyses reveal crosstalk between the Hippo and immune signaling pathways in the tumor microenvironment

et al. 2021

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“…Ni et al, have demonstrated that loss of YAP results in dysfunctional Treg cells failing to inhibit anti-tumor immunity or elicit tumor growth in mice [8]. Additionally, YAP de ciency in T cells enhances T-cell activation, differentiation, and function, as well as improving T-cell responses in cancer [30]. By contrast, the results obtained from the present study revealed that YAP could potentiate Th17 cell differentiation both in PBMCs and asthma mice.…”

Section: Discussioncontrasting

confidence: 73%

“…Whereas, YAP is known to function as an ampli er of the regulatory T cells Treg-reinforcing pathway, holding signi cant potential as an anticancer immunotherapeutic target [8]. In addition to that, loss of YAP in T cells is known to result in enhanced T-cell activation, differentiation, and function, which translates in vivo to an improved ability for T cells to in ltrate and repress the development of tumors [30]. The aforementioned ndings and results explained the promoting role of YAP/HIF-1α in enhancing differentiation of Th17 cells.…”

Section: Discussionmentioning

confidence: 99%

The YAP/HIF-1α/miR-182/EGR2 Axis is Implicated in Asthma Severity by Control of Th17 Cell Differentiation

Zhou

Zhang

et al. 2020

Preprint

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Background: Asthma is a heterogeneous chronic inflammatory disease of the airways, with reversible airflow limitations and airway remodeling. T helper 17 (Th17) cells play an important role in the pathogenesis of allergic asthma. However, there is hitherto little data about signaling pathways controlling Th17 cell differentiation in asthma. The aim of this study was to ascertain whether the YAP/HIF-1α/miR-182/EGR2 axis underpins Th17 cell differentiation and asthma severity.Methods: The study included 29 pediatric patients with asthma, 22 healthy volunteers, ovalbumin (OVA)-induced murine asthma models, and mouse naive CD4+ T. The subpopulation of Th17 cells was examined by flow cytometry. The level of IL-17A was determined by ELISA method. ChIP-qPCR assay and dual-luciferase reporter gene assay were performed to examine interaction between HIF-1α and miR-182, miR-182 and EGR2.Results: YAP, HIF-1α, and miR-182 were found to be up-regulated but EGR2 was down-regulated in human and mouse peripheral blood mononuclear cells (PBMCs) in the context of asthma. Abundant expression of YAP and HIF-1α promoted miR-182 expression and then inhibited EGR2, a target of miR-182, thus enhancing Th17 differentiation and deteriorating asthma and lipid metabolism dysfunction. In addition, in vivo findings revealed that over-expression of EGR2 undermined the promoting effect of the YAP/HIF-1α/miR-182 axis on asthma and lipid metabolism dysfunction.Conclusion: These results shed light on that the activation of the YAP/HIF-1α/miR-182/EGR2 axis may promote Th17 cell differentiation, exacerbate asthma development, and aggravate lipid metabolism dysfunction, providing a potential therapeutic target in asthma.

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“…Verteporfin, a YAP1 inhibitor to disrupt the interaction between YAP/TAZ and TEAD complex, increased the percentage of CD8 + T cells in liver tumor niche in mice. Consistently, verteporfin treatment increased T cell activation without significant effect on T cell proliferation (Stampouloglou et al 2020). Collectively, disruption of YAP1 in liver tumor cells recruits CD8 + T cells to tumor niche.…”

Section: Discussionmentioning

confidence: 60%

“…Collectively, disruption of YAP1 in liver tumor cells recruits CD8 + T cells to tumor niche. Meanwhile, YAP1 in T cells is elevated upon T-cell activation, and deletion of YAP1 in T cells promotes T-cell infiltration into the local tumor niche (Stampouloglou et al 2020). Therefore, we considered that YAP1 inhibitor reduced PD-L1 expression on tumor and increase T cell recruitment.…”

Section: Discussionmentioning

confidence: 99%

Dihydroartemisinin broke immune evasion through YAP1/JAK1/STAT1, 3 pathways to enhance anti-PD-1 therapy in hepatocellular carcinoma

Peng

Shi

et al. 2021

Preprint

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The efficacy of anti-PD-1 therapy is not as expected in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) was overexpressed and activated in HCC. This study aimed to investigate the potential mechanism and inhibitor of YAP1 on immune evasion, and promote anti-PD-1 therapy in HCC. Here, we showed that dihydroartemisinin (DHA), an FDA approved drug, directly suppressed YAP1 expression, leading to break immune evasion in liver tumor niche, characterized by decreased PD-L1 in liver tumor cells and increased CD8+ T cell infiltration. Mechanismly, YAP1 is not only directly related to PD-L1, but also involved in activating the JAK1/STAT1, 3 pathways. Moreover, Yap1 knockout elevated CD4+ and CD8+ T cells in liver tumor niche of Yap1LKO mice. Consistently, verteporfin, YAP1 inhibitor, decreased TGF-β in liver tumor niche and exhausted CD8+ T cells in spleen. Furthermore, DHA combined with anti-PD-1 treatment promoted CD4+ T cell infiltration in the spleen and CD8+ T cells in tumor tissues. Thus, we provide a new combined therapeutic strategy for anti-PD-1 with DHA, a potent YAP1 inhibitor, in HCC.

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Yap suppresses T cell function and infiltration in the tumor microenvironment

Cited by 8 publications

References 77 publications

Pan‐cancer multi‐omics analyses reveal crosstalk between the Hippo and immune signaling pathways in the tumor microenvironment

Pan‐cancer multi‐omics analyses reveal crosstalk between the Hippo and immune signaling pathways in the tumor microenvironment

The YAP/HIF-1α/miR-182/EGR2 Axis is Implicated in Asthma Severity by Control of Th17 Cell Differentiation

Dihydroartemisinin broke immune evasion through YAP1/JAK1/STAT1, 3 pathways to enhance anti-PD-1 therapy in hepatocellular carcinoma

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