YAP-Induced PD-L1 Expression Drives Immune Evasion in BRAFi-Resistant Melanoma

Kim, Min Hwan; Kim, Chang Gon; Kim, Sang Kyum; Shin, Sang Joon; Choe, Eun Ah; Park, Su–Hyung; Shin, Eui‐Cheol; Kim, Joon

doi:10.1158/2326-6066.cir-17-0320

Cited by 176 publications

(161 citation statements)

References 50 publications

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“…YAP/TAZ levels were decreased using siRNA and PD‐L1 expression was assessed after TGFβ treatment. As shown in FigureB, YAP/TAZ knockdown prevented TGFβ stimulated PD‐L1 expression in both human and murine fibroblasts, consistent with previous reports that PD‐L1 is a direct transcriptional target of YAP/TAZ in several tumor models …”

Section: Resultssupporting

confidence: 91%

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Transforming growth factor beta induces fibroblasts to express and release the immunomodulatory protein PD‐L1 into extracellular vesicles

et al. 2019

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Transforming growth factor-beta (TGFβ) is an enigmatic protein with various roles in healthy tissue homeostasis/development as well as the development or progression of cancer, wound healing, fibrotic disorders, and immune modulation, to name a few. As TGFβ is causal to various fibroproliferative disorders featuring localized or systemic tissue/organ fibrosis as well as the activated stroma observed in various malignancies, characterizing the pathways and players mediating its action is fundamental. In the current study, we found that TGFβ induces the expression of the immunoinhibitory molecule Programed death-ligand 1 (PD-L1) in human and murine fibroblasts in a Smad2/3-and YAP/TAZ-dependent manner. Furthermore, PD-L1 knockdown decreased the TGFβ-dependent induction of extracellular matrix proteins, including collagen Iα1 (colIα1) and alpha-smooth muscle actin (α-SMA), and cell migration/wound healing. In addition to an endogenous role for PD-L1 in profibrotic TGFβ signaling, TGFβ stimulated-human lung fibroblast-derived PD-L1 into extracellular vesicles (EVs) capable of inhibiting T cell proliferation in response to T cell receptor stimulation and mediating fibroblast cell migration. These findings provide new insights and potential targets for a variety of fibrotic and malignant diseases. K E Y W O R D Sfibroblast, checkpoint inhibitor, extracellular vesicles, signaling 2214 | KANG et Al. | 2223 KANG et Al. F I G U R E 6EVs from TGFβ treated fibroblasts inhibit T cell proliferation and cell migration. A, MRC5 cultures were treated in the absence(−) or presence (+) of TGFβ (10 ng/mL) for 3 days. Following the collection of the supernatant for EV isolation, the cells were lysed, and both were assessed for expression of PD-L1 or the EV-associated protein CD63 by Western blotting (representative of 3 independent experiments). B, EV particle size distribution was identified through nanoparticle tracking analysis and processed with NTA software (NanoSight). C, EVs were purified from MRC5 cells cultured in the absence (−) or presence (+) of TGFβ as in (A). Peripheral blood mononuclear cells (n = 5 volunteers) were then treated with anti-CD3 (+αCD3; 500 ng/mL) to activate T cell proliferation and incubated for 6 days with no EVs, EVs (10 μg/mL) isolated from cells ± TGFβ, or EVs isolated from cells ± TGFβ ± blocking antibody to PD-L1 (10 μg/mL Avelumab). The percent change in proliferation, measured by carboxyfluorescein diacetate succinimidyl ester (CFSE) content, compared to anti-CD3 treatment alone is shown. D, (Top 2 panels) Transwell invasion assays were performed in MRC5 cells treated in 0.1% FBS/DME alone (Con) or supplemented with 5 ng/mL TGFβ for 18 hours as described in Materials and Methods. (Bottom 3 panels) MRC5 cells were assessed as in the top panels except that the 0.1% FBS/DME contained EVs (10 μg/mL) isolated from MRC5 cells ± TGFβ or MRC5 cells which had been treated with siRNA to PD-L1 and then stimulated with TGFβ. E, Quantitation of transwell migration of cells treated in (D). Data reflect mean ±...

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Section: Resultssupporting

confidence: 91%

“…As shown in Figure5B, YAP/ TAZ knockdown prevented TGFβ stimulated PD-L1 expression in both human and murine fibroblasts, consistent with previous reports that PD-L1 is a direct transcriptional target of YAP/TAZ in several tumor models. [47][48][49]…”

Section: Yap/taz Regulates Pd-l1 Expression By Tgfβmentioning

confidence: 99%

Transforming growth factor beta induces fibroblasts to express and release the immunomodulatory protein PD‐L1 into extracellular vesicles

et al. 2019

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“…Indeed, the expression of miR-130a mimic or miR-130a sponge suppressed or enhanced VGLL4 and PD-L1 levels, respectively, in A549 cells (Fig 6A-C). Consistent with previous reports Lee et al, 2017;Miao et al, 2017;Janse van Rensburg et al, 2018;Kim et al, 2018), we observed an increased PD-L1 mRNA level when YAP5SA, a transcriptionally active and Hippo pathway-resistant YAP mutant, was expressed in A549 cells (Fig EV5B). Consistent with previous reports Lee et al, 2017;Miao et al, 2017;Janse van Rensburg et al, 2018;Kim et al, 2018), we observed an increased PD-L1 mRNA level when YAP5SA, a transcriptionally active and Hippo pathway-resistant YAP mutant, was expressed in A549 cells (Fig EV5B).…”

Section: Yap Inhibits Ifnc-inducible Pd-l1 Expressionsupporting

confidence: 92%

“…Recently, several studies suggest that YAP/TAZ promote PD-L1 expression through TEAD-mediated transcriptional regulation Lee et al, 2017;Miao et al, 2017;Janse van Rensburg et al, 2018;Kim et al, 2018). Interestingly, one study showed that VGLL4 expression is repressed by YAP/TEAD transcriptional complex through miR-130a , which promotes us to test whether miR-130a and YAP could suppress IFNc-inducible PD-L1 expression.…”

Section: Yap Inhibits Ifnc-inducible Pd-l1 Expressionmentioning

confidence: 99%

“…Many studies reported that the dysregulation of several oncogenic or tumor-suppressive pathways constitutively activates the expression of PD-L1, suggesting that this is a general mechanism of tumorigenesis. PTEN deletions, PI3K/AKT mutations (Parsa et al, 2007;Lastwika et al, 2016), EGFR mutations (Akbay et al, 2013), MYC overexpression (Casey et al, 2016), CDK5 disruption (Dorand et al, 2016), and YAP/TAZ activation Lee et al, 2017;Miao et al, 2017;Janse van Rensburg et al, 2018;Kim et al, 2018) represent a rapidly growing list of genetic mechanisms of constitutive PD-L1 expression. Expression of PD-L1 can be induced by many cytokines, of which interferon-gamma (IFNc) is the most potent via JAK1/2-STAT1/2/3-IRF1 signaling axis, with IRF1 binding to PD-L1 promoter (Dong et al, 2002;Loke & Allison, 2003;Lee et al, 2006;Garcia-Diaz et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Loss of VGLL 4 suppresses tumor PD ‐L1 expression and immune evasion

Deng

et al. 2018

The EMBO Journal

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Targeting immune checkpoints, such as PD‐L1 and its receptor PD‐1, has opened a new avenue for treating cancers. Understanding the regulatory mechanism of PD‐L1 and PD‐1 will improve the clinical response rate and efficacy of PD‐1/PD‐L1 blockade in cancer patients and the development of combinatorial strategies. VGLL4 inhibits YAP‐induced cell proliferation and tumorigenesis through competition with YAP for binding to TEADs. However, whether VGLL4 has a role in anti‐tumor immunity is largely unknown. Here, we found that disruption of Vgll4 results in potent T cell‐mediated tumor regression in murine syngeneic models. VGLL4 deficiency reduces PD‐L1 expression in tumor cells. VGLL4 interacts with IRF2BP2 and promotes its protein stability through inhibiting proteasome‐mediated protein degradation. Loss of IRF2BP2 results in persistent binding of IRF2, a transcriptional repressor, to PD‐L1 promoter. In addition, YAP inhibits IFNγ‐inducible PD‐L1 expression partially through suppressing the expression of VGLL4 and IRF1 by YAP target gene miR‐130a. Our study identifies VGLL4 as an important regulator of PD‐L1 expression and highlights a central role of VGLL4 and YAP in the regulation of tumor immunity.

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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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YAP-Induced PD-L1 Expression Drives Immune Evasion in BRAFi-Resistant Melanoma

Cited by 176 publications

References 50 publications

Transforming growth factor beta induces fibroblasts to express and release the immunomodulatory protein PD‐L1 into extracellular vesicles

Transforming growth factor beta induces fibroblasts to express and release the immunomodulatory protein PD‐L1 into extracellular vesicles

Loss of VGLL 4 suppresses tumor PD ‐L1 expression and immune evasion

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

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