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

Abstract:

:Activation of YAP, a Hippo pathway effector, is an important resistance mechanism to BRAF inhibitor (BRAFi) in melanoma. Emerging evidence also suggests that YAP is involved in suppression of the antitumor immune response. However, the potential direct impact of YAP activity on cytotoxic T-cell immune responses has not been explored yet. Here, we show that BRAFi-resistant melanoma cells evade CD8+ T-cell immune responses in a PD-L1-dependent manner by activating YAP, which synchronously supports melanoma cell survival upon BRAF inhibition. PD-L1 expression is elevated in BRAFi-resistant melanoma cells, in which YAP is robustly activated, and YAP knockdown decreases PD-L1 expression. In addition, constitutively active YAP (YAP-5SA) increases PD-L1 expression by binding to an upstream enhancer of the PD-L1 gene and potentiating its transcription. Both BRAFi-resistant and YAP-5SA-expressing melanoma cells suppress the cytotoxic function and cytokine production of Melan-A-specific CD8+ T cells, whereas anti-PD-1 antibody reverses the YAP-mediated T-cell suppression. Moreover, nuclear enrichment of YAP in clinical melanoma samples correlates with increased PD-L1 expression. Our findings show that YAP directly mediates evasion of cytotoxic T-cell immune responses in BRAFi-resistant melanoma cells by upregulating PD-L1, and targeting of YAP-mediated immune evasion may improve prognosis of melanoma patients. Cancer Immunol Res; 6(3); 255-66. ©2018 AACR.

journal_name

Cancer Immunol Res

authors

Kim MH,Kim CG,Kim SK,Shin SJ,Choe EA,Park SH,Shin EC,Kim J

doi

10.1158/2326-6066.CIR-17-0320

subject

Has Abstract

pub_date

2018-03-01 00:00:00

pages

255-266

issue

3

eissn

2326-6066

issn

2326-6074

pii

2326-6066.CIR-17-0320

journal_volume

6

pub_type

杂志文章
  • Highly optimized DNA vaccine targeting human telomerase reverse transcriptase stimulates potent antitumor immunity.

    abstract::High levels of human telomerase reverse transcriptase (hTERT) are detected in more than 85% of human cancers. Immunologic analysis supports that hTERT is a widely applicable target recognized by T cells and can be potentially studied as a broad cancer immunotherapeutic, or a unique line of defense against tumor recurr...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-13-0001

    authors: Yan J,Pankhong P,Shin TH,Obeng-Adjei N,Morrow MP,Walters JN,Khan AS,Sardesai NY,Weiner DB

    更新日期:2013-09-01 00:00:00

  • Antitumor T-cell Immunity Contributes to Pancreatic Cancer Immune Resistance.

    abstract::Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Pancreatic tumors are minimally infiltrated by T cells and are largely refractory to immunotherapy. Accordingly, the role of T-cell immunity in pancreatic cancer has been somewhat overlooked. Here, we hypothesized ...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-20-0272

    authors: Ajina R,Malchiodi ZX,Fitzgerald AA,Zuo A,Wang S,Moussa M,Cooper CJ,Shen Y,Johnson QR,Parks JM,Smith JC,Catalfamo M,Fertig EJ,Jablonski SA,Weiner LM

    更新日期:2021-01-28 00:00:00

  • Improved Antitumor Efficacy of Chimeric Antigen Receptor T Cells that Secrete Single-Domain Antibody Fragments.

    abstract::Chimeric antigen receptor (CAR) T-cell therapy is effective in the treatment of cancers of hematopoietic origin. In the immunosuppressive solid tumor environment, CAR T cells encounter obstacles that compromise their efficacy. We developed a strategy to address these barriers by having CAR T cells secrete single-domai...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-19-0734

    authors: Xie YJ,Dougan M,Ingram JR,Pishesha N,Fang T,Momin N,Ploegh HL

    更新日期:2020-04-01 00:00:00

  • Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor.

    abstract::Despite the rapid progress in the development of novel adoptive T-cell therapies, the clinical benefits in treatment of established tumors have remained modest. Several immune evasion mechanisms hinder T-cell entry into tumors and their activity within the tumor. Of note, oncolytic adenoviruses are intrinsically immun...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-14-0220-T

    authors: Tähtinen S,Grönberg-Vähä-Koskela S,Lumen D,Merisalo-Soikkeli M,Siurala M,Airaksinen AJ,Vähä-Koskela M,Hemminki A

    更新日期:2015-08-01 00:00:00

  • Human NKp44+ Group 3 Innate Lymphoid Cells Associate with Tumor-Associated Tertiary Lymphoid Structures in Colorectal Cancer.

    abstract::Innate lymphoid cells (ILC) are responsible for mucosal tissue homeostasis and are involved in the progression and suppression of several types of cancer. However, the effects of ILCs on colorectal cancer are poorly understood. We characterized human ILCs in normal colon and colorectal cancer tissue, investigating the...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-19-0775

    authors: Ikeda A,Ogino T,Kayama H,Okuzaki D,Nishimura J,Fujino S,Miyoshi N,Takahashi H,Uemura M,Matsuda C,Yamamoto H,Takeda K,Mizushima T,Mori M,Doki Y

    更新日期:2020-06-01 00:00:00

  • Activated Eosinophils Exert Antitumorigenic Activities in Colorectal Cancer.

    abstract::Immunotherapies targeting T lymphocytes are revolutionizing cancer therapy but only benefit a subset of patients, especially in colorectal cancer. Thus, additional insight into the tumor microenvironment (TME) is required. Eosinophils are bone marrow-derived cells that have been largely studied in the context of aller...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-18-0494

    authors: Reichman H,Itan M,Rozenberg P,Yarmolovski T,Brazowski E,Varol C,Gluck N,Shapira S,Arber N,Qimron U,Karo-Atar D,Lee JJ,Munitz A

    更新日期:2019-03-01 00:00:00

  • Urinary Bladder Cancer Tregs Suppress MMP2 and Potentially Regulate Invasiveness.

    abstract::Regulatory T cells (Treg) have long been considered one-sided suppressors of antitumor immune responses and hence associated with poor patient outcome in cancer. However, evidence is mounting of a paradoxical positive prognostic effect of Tregs on certain malignancies, including urinary bladder cancer (UBC). This disc...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-17-0466

    authors: Winerdal ME,Krantz D,Hartana CA,Zirakzadeh AA,Linton L,Bergman EA,Rosenblatt R,Vasko J,Alamdari F,Hansson J,Holmström B,Johansson M,Winerdal M,Marits P,Sherif A,Winqvist O

    更新日期:2018-05-01 00:00:00

  • Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade.

    abstract::Blockade of the pathway including programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) has produced clinical benefits in patients with a variety of cancers. Elevated levels of soluble PD-L1 (sPD-L1) have been associated with worse prognosis in renal cell carcinoma and multiple myel...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-16-0329

    authors: Zhou J,Mahoney KM,Giobbie-Hurder A,Zhao F,Lee S,Liao X,Rodig S,Li J,Wu X,Butterfield LH,Piesche M,Manos MP,Eastman LM,Dranoff G,Freeman GJ,Hodi FS

    更新日期:2017-06-01 00:00:00

  • IL1α Antagonizes IL1β and Promotes Adaptive Immune Rejection of Malignant Tumors.

    abstract::We assessed the contribution of IL1 signaling molecules to malignant tumor growth using IL1β-/-, IL1α-/-, and IL1R1-/- mice. Tumors grew progressively in IL1R-/- and IL1α-/- mice but were often absent in IL1β-/- mice. This was observed whether tumors were implanted intradermally or injected intravenously and was true ...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-19-0552

    authors: Tian T,Lofftus S,Pan Y,Stingley CA,King SL,Zhao J,Pan TY,Lock R,Marglous JW,Liu K,Widlund HR,Fuhlbrigge RC,Cichowski K,Kupper TS

    更新日期:2020-05-01 00:00:00

  • Tumor Cell-Intrinsic USP22 Suppresses Antitumor Immunity in Pancreatic Cancer.

    abstract::Although immune checkpoint blockade (ICB) improves clinical outcome in several types of malignancies, pancreatic ductal adenocarcinoma (PDA) remains refractory to this therapy. Preclinical studies have demonstrated that the relative abundance of suppressive myeloid cells versus cytotoxic T cells determines the efficac...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-19-0661

    authors: Li J,Yuan S,Norgard RJ,Yan F,Yamazoe T,Blanco A,Stanger BZ

    更新日期:2020-03-01 00:00:00

  • Clinical Response of a Patient to Anti-PD-1 Immunotherapy and the Immune Landscape of Testicular Germ Cell Tumors.

    abstract::Anti-Programed Death 1 (PD-1) is standard immunotherapy for multiple cancers, and the expression of one of its ligands, PD-L1, has been described in germ cell tumors (GCT). Neither the clinical activity of anti-PD-1 nor the incidence of an immunoresponsive tumor microenvironment has been described for GCTs. A patient ...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-16-0087

    authors: Shah S,Ward JE,Bao R,Hall CR,Brockstein BE,Luke JJ

    更新日期:2016-11-01 00:00:00

  • Reduced Breast Tumor Growth after Immunization with a Tumor-Restricted MUC1 Glycopeptide Conjugated to Tetanus Toxoid.

    abstract::Preventive vaccination against tumor-associated endogenous antigens is considered to be an attractive strategy for the induction of a curative immune response concomitant with a long-lasting immunologic memory. The mucin MUC1 is a promising tumor antigen, as its tumor-associated form differs from the glycoprotein form...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-18-0256

    authors: Stergiou N,Gaidzik N,Heimes AS,Dietzen S,Besenius P,Jäkel J,Brenner W,Schmidt M,Kunz H,Schmitt E

    更新日期:2019-01-01 00:00:00

  • Reflections on the Histopathology of Tumor-Infiltrating Lymphocytes in Melanoma and the Host Immune Response.

    abstract::In the past five decades, the role for lymphocytes in host immune response to tumors has been shown, at least in some patients, to be a critical component in disease prognosis. Also, the heterogeneity of lymphocytes has been documented, including the existence of regulatory T cells that suppress the immune response. A...

    journal_title:Cancer immunology research

    pub_type: 杂志文章,评审

    doi:10.1158/2326-6066.CIR-15-0143

    authors: Mihm MC Jr,Mulé JJ

    更新日期:2015-08-01 00:00:00

  • Durable Clinical Benefit in Metastatic Renal Cell Carcinoma Patients Who Discontinue PD-1/PD-L1 Therapy for Immune-Related Adverse Events.

    abstract::The current standard of care for treatment of metastatic renal cell carcinoma (mRCC) patients is PD-1/PD-L1 inhibitors until progression or toxicity. Here, we characterize the clinical outcomes for 19 mRCC patients who experienced an initial clinical response (any degree of tumor shrinkage), but after immune-related a...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-17-0220

    authors: Martini DJ,Hamieh L,McKay RR,Harshman LC,Brandao R,Norton CK,Steinharter JA,Krajewski KM,Gao X,Schutz FA,McGregor B,Bossé D,Lalani AA,De Velasco G,Michaelson MD,McDermott DF,Choueiri TK

    更新日期:2018-04-01 00:00:00

  • Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade.

    abstract::Immune checkpoint inhibitors are promising treatments for patients with a variety of malignancies. Toward understanding the determinants of response to immune checkpoint inhibitors, it was previously demonstrated that the presence of somatic mutations is associated with benefit from checkpoint inhibition. A hypothesis...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-16-0019

    authors: Nathanson T,Ahuja A,Rubinsteyn A,Aksoy BA,Hellmann MD,Miao D,Van Allen E,Merghoub T,Wolchok JD,Snyder A,Hammerbacher J

    更新日期:2017-01-01 00:00:00

  • Possible Interaction of Anti-PD-1 Therapy with the Effects of Radiosurgery on Brain Metastases.

    abstract::Delayed radiation-induced vasculitic leukoencephalopathy related to stereotactic radiosurgery (SRS) of brain metastases has been reported to manifest clinically 9 to 18 months after treatment. Immune-modulating therapies have been introduced to treatment regimens for malignancies with metastatic predilection to the br...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-15-0238

    authors: Alomari AK,Cohen J,Vortmeyer AO,Chiang A,Gettinger S,Goldberg S,Kluger HM,Chiang VL

    更新日期:2016-06-01 00:00:00

  • The Antigen ASB4 on Cancer Stem Cells Serves as a Target for CTL Immunotherapy of Colorectal Cancer.

    abstract::Colorectal cancer consists of a small number of cancer stem cells (CSC) and many non-CSCs. Although rare in number, CSCs are a target for cancer therapy, because they survive conventional chemo- and radiotherapies and perpetuate tumor formation in vivo In this study, we conducted an HLA ligandome analysis to survey HL...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-17-0518

    authors: Miyamoto S,Kochin V,Kanaseki T,Hongo A,Tokita S,Kikuchi Y,Takaya A,Hirohashi Y,Tsukahara T,Terui T,Ishitani K,Hata F,Takemasa I,Miyazaki A,Hiratsuka H,Sato N,Torigoe T

    更新日期:2018-03-01 00:00:00

  • Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.

    abstract::The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, I...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-13-0136

    authors: Charbonneau B,Moysich KB,Kalli KR,Oberg AL,Vierkant RA,Fogarty ZC,Block MS,Maurer MJ,Goergen KM,Fridley BL,Cunningham JM,Rider DN,Preston C,Hartmann LC,Lawrenson K,Wang C,Tyrer J,Song H,deFazio A,Johnatty SE,Doher

    更新日期:2014-04-01 00:00:00

  • Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma.

    abstract::Ipilimumab and radiotherapy are commonly used to treat unresectable and metastatic melanoma. Results from preclinical studies and case reports suggest a biologic interaction between these two treatments. To understand the clinical implications of the interaction, we carried out a retrospective study reviewing records ...

    journal_title:Cancer immunology research

    pub_type: 杂志文章,评审

    doi:10.1158/2326-6066.CIR-13-0082

    authors: Barker CA,Postow MA,Khan SA,Beal K,Parhar PK,Yamada Y,Lee NY,Wolchok JD

    更新日期:2013-08-01 00:00:00

  • Pathogen-driven cancers and emerging immune therapeutic strategies.

    abstract::Infectious agents play an etiologic role in approximately 20% of cancer cases worldwide. Eleven pathogens (seven viruses, three parasites, and one bacterium) are known to contribute to oncogenesis either directly via the expression of their protein products or indirectly via chronic inflammation. Although prevention o...

    journal_title:Cancer immunology research

    pub_type: 杂志文章,评审

    doi:10.1158/2326-6066.CIR-13-0179

    authors: Vandeven N,Nghiem P

    更新日期:2014-01-01 00:00:00

  • STAT3 in CD8+ T Cells Inhibits Their Tumor Accumulation by Downregulating CXCR3/CXCL10 Axis.

    abstract::One of the obstacles for cancer immunotherapy is the inefficiency of CD8(+) T-cell recruitment to tumors. STAT3 has been shown to suppress CD8(+) T-cell antitumor functions in various cancer models, in part by restricting accumulation of CD8(+) T cells. However, the underlying molecular mechanism by which STAT3 in CD8...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-15-0014

    authors: Yue C,Shen S,Deng J,Priceman SJ,Li W,Huang A,Yu H

    更新日期:2015-08-01 00:00:00

  • Translating Science into Survival: Report on the Second International Cancer Immunotherapy Conference.

    abstract::On September 25-28, 2016, in New York City, the Second International Cancer Immunotherapy Conference was cohosted by the Cancer Research Institute, the American Association for Cancer Research, the Association for Cancer Immunotherapy, and the European Academy of Tumor Immunology. This exciting conference brought toge...

    journal_title:Cancer immunology research

    pub_type:

    doi:10.1158/2326-6066.CIR-16-0276

    authors: Brodsky AN,Hubbard-Lucey VM

    更新日期:2016-12-01 00:00:00

  • Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune-Tumor Interactions: Engage, Expand, Enable.

    abstract::Immunotherapy of immunologically cold solid tumors may require multiple agents to engage immune effector cells, expand effector populations and activities, and enable immune responses in the tumor microenvironment (TME). To target these distinct phenomena, we strategically chose five clinical-stage immuno-oncology age...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-20-0638

    authors: Fabian KP,Malamas AS,Padget MR,Solocinski K,Wolfson B,Fujii R,Abdul Sater H,Schlom J,Hodge JW

    更新日期:2020-12-22 00:00:00

  • Macropinocytosis of Nab-paclitaxel Drives Macrophage Activation in Pancreatic Cancer.

    abstract::Pancreatic cancer is a devastating disease that is largely refractory to currently available treatment strategies. Therapeutic resistance is partially attributed to the dense stromal reaction of pancreatic ductal adenocarcinoma tumors that includes a pervasive infiltration of immunosuppressive (M2) macrophages. Nab-pa...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-16-0125

    authors: Cullis J,Siolas D,Avanzi A,Barui S,Maitra A,Bar-Sagi D

    更新日期:2017-03-01 00:00:00

  • A Mechanism of Resistance to Antibody-Targeted Immune Attack.

    abstract::Targeted monoclonal antibody therapy is a promising therapeutic strategy for cancer, and antibody-dependent cell-mediated cytotoxicity (ADCC) represents a crucial mechanism underlying these approaches. The majority of patients have limited responses to monoclonal antibody therapy due to the development of resistance. ...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-18-0266

    authors: Aldeghaither DS,Zahavi DJ,Murray JC,Fertig EJ,Graham GT,Zhang YW,O'Connell A,Ma J,Jablonski SA,Weiner LM

    更新日期:2019-02-01 00:00:00

  • Cancer-testis antigen expression in digestive tract carcinomas: frequent expression in esophageal squamous cell carcinoma and its precursor lesions.

    abstract::Cancer-testis (CT) antigens are attractive tumor antigens for cancer immunotherapy. They comprise a group of proteins normally expressed in germ cells and aberrantly activated in a variety of human cancers. The protein expression of eight cancer-testis antigens [MAGEA, NY-ESO-1, GAGE, MAGEC1 (CT7), MAGEC2 (CT10), CT45...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-13-0124

    authors: Chen YT,Panarelli NC,Piotti KC,Yantiss RK

    更新日期:2014-05-01 00:00:00

  • The path to reactivation of antitumor immunity and checkpoint immunotherapy.

    abstract::Cancer immunology has recently made major therapeutic inroads that represent clinical application of basic insights into mechanisms that govern immunity against tumors. Research into fundamental elements of T-cell and natural killer-cell biology, including the basis of antigen recognition, activation, proliferation, a...

    journal_title:Cancer immunology research

    pub_type: 杂志文章,评审

    doi:10.1158/2326-6066.CIR-14-0153

    authors: Kim HJ,Cantor H

    更新日期:2014-10-01 00:00:00

  • Targeted Deletion of CXCR2 in Myeloid Cells Alters the Tumor Immune Environment to Improve Antitumor Immunity.

    abstract::Recruitment of myeloid-derived suppressor cells (MDSC) into the tumor microenvironment (TME) contributes to cancer immune evasion. MDSCs express the chemokine receptor CXCR2, and inhibiting CXCR2 suppresses the recruitment of MDSCs into the tumor and the premetastatic niche. Here, we compared the growth and metastasis...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-20-0312

    authors: Yang J,Yan C,Vilgelm AE,Chen SC,Ayers GD,Johnson CA,Richmond A

    更新日期:2020-11-11 00:00:00

  • STAT1-Induced HLA Class I Upregulation Enhances Immunogenicity and Clinical Response to Anti-EGFR mAb Cetuximab Therapy in HNC Patients.

    abstract::The goal of this study was to characterize the molecular mechanisms underlying cetuximab-mediated upregulation of HLA class I antigen-processing machinery components in head and neck cancer (HNC) cells and to determine the clinical significance of these changes in cetuximab-treated HNC patients. Flow cytometry, signal...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-15-0053

    authors: Srivastava RM,Trivedi S,Concha-Benavente F,Hyun-Bae J,Wang L,Seethala RR,Branstetter BF 4th,Ferrone S,Ferris RL

    更新日期:2015-08-01 00:00:00

  • Affinity enhancement of antibodies: how low-affinity antibodies produced early in immune responses are followed by high-affinity antibodies later and in memory B-cell responses.

    abstract::The antibodies produced initially in response to most antigens are high molecular weight (MW) immunoglobulins (IgM) with low affinity for the antigen, while the antibodies produced later are lower MW classes (e.g., IgG and IgA) with, on average, orders of magnitude higher affinity for that antigen. These changes, ofte...

    journal_title:Cancer immunology research

    pub_type: 杂志文章,评审

    doi:10.1158/2326-6066.CIR-14-0029

    authors: Eisen HN

    更新日期:2014-05-01 00:00:00