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  • 1
    Online Resource
    Online Resource
    The impact of FGFR1 and FRS2α expression on sorafenib treatment in metastatic renal cell carcinoma
    Springer Science and Business Media LLC ; 2015
    In:  BMC Cancer Vol. 15, No. 1 ( 2015-12)
    Details
    In: BMC Cancer, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2015-12)
    Type of Medium: Online Resource
    ISSN: 1471-2407
    URL: Article
    DOI: 10.1186/s12885-015-1302-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
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  • 2
    Online Resource
    Online Resource
    Resistance to Antiangiogenic Therapy Is Associated with an Immunosuppressive Tumor Microenvironment in Metastatic Renal Cell Carcinoma
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Immunology Research Vol. 3, No. 9 ( 2015-09-01), p. 1017-1029
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 3, No. 9 ( 2015-09-01), p. 1017-1029
    Abstract: Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and antiangiogenic therapy is the current mainstay of treatment. Patients with RCC develop innate or adaptive resistance to antiangiogenic therapy. There is a need to identify biomarkers that predict therapeutic resistance and guide combination therapy. We assessed the interaction between antiangiogenic therapy and the tumor immune microenvironment and determined their impact on clinical outcome. We found that antiangiogenic therapy–treated RCC primary tumors showed increased infiltration of CD4+ and CD8+ T lymphocytes, which was inversely related to patient overall survival and progression-free survival. Furthermore, specimens from patients treated with antiangiogenic therapy showed higher infiltration of CD4+FOXP3+ regulatory T cells and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T-lymphocyte infiltration and were negatively related to patient survival. Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Results from this study indicate that antiangiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to antiangiogenic therapy and will guide the development of combination therapy with PD-1/PD-L1–blocking agents. Cancer Immunol Res; 3(9); 1017–29. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-14-0244
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2732517-9
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  • 3
    Online Resource
    Online Resource
    PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma
    Springer Science and Business Media LLC ; 2020
    In:  Nature Communications Vol. 11, No. 1 ( 2020-05-01)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-05-01)
    Abstract: A non-immunogenic tumor microenvironment (TME) is a significant barrier to immune checkpoint blockade (ICB) response. The impact of Polybromo-1 ( PBRM1 ) on TME and response to ICB in renal cell carcinoma (RCC) remains to be resolved. Here we show that PBRM1 / Pbrm1 deficiency reduces the binding of brahma-related gene 1 (BRG1) to the IFNγ receptor 2 ( Ifngr2 ) promoter, decreasing STAT1 phosphorylation and the subsequent expression of IFNγ target genes. An analysis of 3 independent patient cohorts and of murine pre-clinical models reveals that PBRM1 loss is associated with a less immunogenic TME and upregulated angiogenesis. Pbrm1 deficient Renca subcutaneous tumors in mice are more resistance to ICB, and a retrospective analysis of the IMmotion150 RCC study also suggests that PBRM1 mutation reduces benefit from ICB. Our study sheds light on the influence of PBRM1 mutations on IFNγ-STAT1 signaling and TME, and can inform additional preclinical and clinical studies in RCC.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-020-15959-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2553671-0
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  • 4
    Online Resource
    Online Resource
    Abstract B48: PBRM1 loss promotes resistance to immunotherapy in RCC
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Immunology Research Vol. 8, No. 4_Supplement ( 2020-04-01), p. B48-B48
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 8, No. 4_Supplement ( 2020-04-01), p. B48-B48
    Abstract: PBRM1 is a subunit of a SWI/SNF chromatin remodeling complex, and more than 30% of clear cell RCCs show PBRM1 mutations. The function of PBRM1 in tumor immune microenvironment, tumor prognosis and response to immune checkpoint therapies still remain unclear. Here we found that Pbrm1 knockout in mouse Renca RCC cells decreased the activity of IFNγ-STAT1 signaling pathway and consequently the expression of chemokines that recruit effector CD8+ T cells. Pbrm1 deficient murine RCC tumors showed reduced infiltration of CD8+ T cells, which was associated with less PD-1 expression. Pbrm1 deficient tumors demonstrated longer latency but they were more resistant to anti-PD1 treatment. This study provided mechanistic insights and therapeutic guideline to manage ccRCC associated with PBRM1 inactivation. Citation Format: Xian-De Liu, Wen Kong, Anh Hoang, Xuesong Zhang, Lijun Zhou, Patrick G. Pilie, Sevinj Isgandrova, Margie M. Moczygemba, Eric Jonasch. PBRM1 loss promotes resistance to immunotherapy in RCC [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B48.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.TUMIMM18-B48
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2732517-9
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  • 5
    Online Resource
    Online Resource
    SETD2 Loss and ATR Inhibition Synergize to Promote cGAS Signaling and Immunotherapy Response in Renal Cell Carcinoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 19 ( 2023-10-02), p. 4002-4015
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 19 ( 2023-10-02), p. 4002-4015
    Abstract: Immune checkpoint blockade (ICB) demonstrates durable clinical benefits in a minority of patients with renal cell carcinoma (RCC). We aimed to identify the molecular features that determine the response and develop approaches to enhance it. Experimental Design: We investigated the effects of SET domain-containing protein 2 (SETD2) loss on the DNA damage response pathway, the cytosolic DNA-sensing pathway, the tumor immune microenvironment, and the response to ataxia telangiectasia and rad3-related (ATR) and checkpoint inhibition in RCC. Results: ATR inhibition activated the cyclic GMP–AMP synthase (cGAS)-interferon regulatory factor 3 (IRF3)–dependent cytosolic DNA-sensing pathway, resulting in the concurrent expression of inflammatory cytokines and immune checkpoints. Among the common RCC genotypes, SETD2 loss is associated with preferential ATR activation and sensitizes cells to ATR inhibition. SETD2 knockdown promoted the cytosolic DNA-sensing pathway in response to ATR inhibition. Treatment with the ATR inhibitor VE822 concurrently upregulated immune cell infiltration and immune checkpoint expression in Setd2 knockdown Renca tumors, providing a rationale for ATR inhibition plus ICB combination therapy. Setd2-deficient Renca tumors demonstrated greater vulnerability to ICB monotherapy or combination therapy with VE822 than Setd2-proficient tumors. Moreover, SETD2 mutations were associated with a higher response rate and prolonged overall survival in patients with ICB-treated RCC but not in patients with non–ICB-treated RCC. Conclusions: SETD2 loss and ATR inhibition synergize to promote cGAS signaling and enhance immune cell infiltration, providing a mechanistic rationale for the combination of ATR and checkpoint inhibition in patients with RCC with SETD2 mutations.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-23-1003
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 6
    Online Resource
    Online Resource
    Abstract 312: Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 312-312
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 312-312
    Abstract: Autophagy is a conserved process involved in lysosomal degradation of protein aggregates and damaged organelles. The role of autophagy in cancer is a topic of intense debate, and the underlying mechanism is still not clear. Here we reported that the hypoxia inducible factor 2α (HIF2α), an oncogenic transcription factor implicated in renal tumorigenesis, was in part constitutively degraded by autophagy. HIF2α interacts with autophagy protein LC3, autophagy receptor p62, and lysosome protein LAMP1. Inhibition of autophagy results in HIF2α accumulation, while induction of autophagy promotes HIF2α degradation. The E3 ubiquitin ligase activity of the von Hippel-Lindau (VHL) is required for autophagic degradation of HIF2α. There is a complementary interaction between the proteasome and autophagy in HIF2α degradation. Autophagy inactivation in ATG5 knockout cells redirects HIF2α to proteasomal degradation, while proteasome inhibition induced autophagy and favored the HIF2α-p62 interaction. Importantly, we reported that clear cell renal cell carcinoma (ccRCC) was frequently associated with mono-allelic loss and/or mutation of autophagy related gene ATG7, and low expression level of autophagy genes correlated with ccRCC progression. This study sheds light on the anticancer role for autophagy in ccRCC tumorigenesis, and reveals constitutive autophagic degradation of HIF2α as a novel tumor suppression mechanism. Citation Format: Xian-De Liu, Jun Yao, Durga N. Tripathi, Zhiyong Ding, Yi Xu, Mianen Sun, Jiangwei Zhang, Shanshan Bai, Peter German, Anh Hoang, Lijun Zhou, Xuesong Zhang, Claudio J. Conti, Eleni Efstathiou, Tony N. Eissa, Gordon B. Mills, Cheryl L. Walker, Eric Jonasch. Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 312. doi:10.1158/1538-7445.AM2014-312
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-312
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
    Online Resource
    Online Resource
    Abstract A147: Sunitinib upregulates IFNγ-STAT1 signaling to modulate the tumor immune microenvironment in renal cell carcinoma
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Immunology Research Vol. 4, No. 1_Supplement ( 2016-01-01), p. A147-A147
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 4, No. 1_Supplement ( 2016-01-01), p. A147-A147
    Abstract: Antiangiogenic therapy is the current mainstay of treatment for renal cell carcinoma (RCC). Recently we reported that antiangiogenic therapy-treated primary tumors demonstrated both increased infiltration of CD4 and CD8 T cells and higher expression of the immune checkpoint ligand PD-L1, all of which were associated with therapy resistance. The underlying mechanism remains unknown. IFNγ-STAT1 signaling pathway drives the expression of both immunosuppressive PD-L1, and immunostimulatory chemoattractants, adhesion molecules and class I antigen presentation components. We studied the effects of sunitinib on the IFNγ-STAT1 signaling pathway. We found that sunitinib treatment magnified IFNγ-induced STAT1 activity. Sunitinib not only increased the activity of janus kinase (JAK) and the tyrosine phosphorylation of STAT1, but also decreased the protein level of PIAS and SOCS, negative regulators of STAT1 signaling. These results indicate that sunitinib treatment potently activates IFNγ-mediated STAT1 signaling by modulating both activators and inhibitors of STAT1. Further investigation is underway into the precise signaling pathways involved in sunitinib mediated regulation of upstream regulators of STAT1, and on the effect of sunitinib mediated STAT1 signaling on other immunostimulatory molecules in the tumor cell. Understanding the impact of STAT1 activation on target proteins after stimulation by antiangiogenic therapy will guide us to develop predictive biomarkers for combination antiangiogenic and immunomodulatory therapy, and devise precise interventions to overcome tumor cell specific immunosuppressive signaling. Citation Format: Xian-De Liu, Anh Hoang, Mianen Sun, Zhou Lijun, Zhiyong Ding, Xuesong Zhang, Shanshan Bai, Nizar Tannir, Eric Jonasch. Sunitinib upregulates IFNγ-STAT1 signaling to modulate the tumor immune microenvironment in renal cell carcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A147.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.CRICIMTEATIAACR15-A147
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2732517-9
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