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Riccardo Mezzadra - One of the best experts on this subject based on the ideXlab platform.
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identification of cmtm6 and cmtm4 as pd L1 Protein regulators
Nature, 2017Co-Authors: Riccardo Mezzadra, Evert De Vries, Meike E.w. Logtenberg, Maarten Slagter, Elisa A. Rozeman, Ingrid Hofland, Wei Wu, Raquel Gomezeerland, Annegien Broeks, Hugo M HorlingsAbstract:The clinical benefit for patients with diverse types of metastatic cancers that has been observed upon blockade of the interaction between PD-1 and PD-L1 has highlighted the importance of this inhibitory axis in the suppression of tumour-specific T-cell responses. Notwithstanding the key role of PD-L1 expression by cells within the tumour micro-environment, our understanding of the regulation of the PD-L1 Protein is limited. Here we identify, using a haploid genetic screen, CMTM6, a type-3 transmembrane Protein of previously unknown function, as a regulator of the PD-L1 Protein. Interference with CMTM6 expression results in impaired PD-L1 Protein expression in all human tumour cell types tested and in primary human dendritic cells. Furthermore, through both a haploid genetic modifier screen in CMTM6-deficient cells and genetic complementation experiments, we demonstrate that this function is shared by its closest family member, CMTM4, but not by any of the other CMTM members tested. Notably, CMTM6 increases the PD-L1 Protein pool without affecting PD-L1 (also known as CD274) transcription levels. Rather, we demonstrate that CMTM6 is present at the cell surface, associates with the PD-L1 Protein, reduces its ubiquitination and increases PD-L1 Protein half-life. Consistent with its role in PD-L1 Protein regulation, CMTM6 enhances the ability of PD-L1-expressing tumour cells to inhibit T cells. Collectively, our data reveal that PD-L1 relies on CMTM6/4 to efficiently carry out its inhibitory function, and suggest potential new avenues to block this pathway.
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Abstract LB-291: Identification of CMTM6 and CMTM4 as PD-L1 Protein regulators
Cancer Research, 2017Co-Authors: Riccardo Mezzadra, Raquel Gomez-eerland, Evert De Vries, Wei Wu, Yanling Xiao, Albert J. R. Heck, Jannie Borst, Thijn R. BrummelkampAbstract:The clinical benefit in patients with diverse types of metastatic cancers that is observed upon blockade of the PD-1 - PD-L1 interaction has highlighted the importance of this inhibitory axis in the suppression of human tumor-specific T cell responses. In spite of the key role of PD-L1 expression by cells within the tumor microenvironment, our understanding of the regulation of the PD-L1 Protein is limited. Using a haploid genetic screen, we here identify CMTM6, a poorly described type 3 transmembrane Protein of previously unknown function, as a regulator of the PD-L1 Protein. Interference with CMTM6 expression results in impaired PD-L1 Protein expression in all tumor cell types tested and also in primary human dendritic cells. Furthermore, through both a haploid genetic modifier screen in CMTM6 deficient cells and genetic complementation experiments, we demonstrate that this function is shared by its closest family member CMTM4, but not by all other CMTM members tested. Notably, CMTM6 increases the PD-L1 Protein pool without affecting PD-L1 transcript levels. Rather, we demonstrate that CMTM6 is present at the cell surface, associates with PD-L1 Protein, and increases PD-L1 Protein half-life. Consistent with this role, T cell inhibitory capacity of PD-L1 expressing tumor cells is enhanced by CMTM6. Collectively, our data reveal that PD-L1 relies on CMTM6/4 to efficiently carry out its inhibitory function, and suggest potential new avenues to block this pathway. [C.S., R.M., and L.T.J. contributed equally to this work. T.R.B. and T.N.M.S. are both corresponding authors.] Citation Format: Chong Sun, Riccardo Mezzadra, Lucas T. Jae, Raquel Gomez-Eerland, Evert de Vries, Wei Wu, Yanling Xiao, Albert J. Heck, Jannie Borst, Thijn R. Brummelkamp, Ton N. Schumacher. Identification of CMTM6 and CMTM4 as PD-L1 Protein regulators [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-291. doi:10.1158/1538-7445.AM2017-LB-291
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Identification of CMTM6 and CMTM4 as PD-L1 Protein regulators
Nature, 2017Co-Authors: Riccardo Mezzadra, Lucas T. Jae, Raquel Gomez-eerland, Evert De Vries, Meike E.w. Logtenberg, Maarten Slagter, Elisa A. Rozeman, Chong Sun, Wei Wu, Ingrid HoflandAbstract:CMTM6 and CMTM4 bind to and stabilize the inhibitory receptor PD-L1 and regulate PD-L1 levels at the surface of human tumour and immune cells.
Ingrid Hofland - One of the best experts on this subject based on the ideXlab platform.
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identification of cmtm6 and cmtm4 as pd L1 Protein regulators
Nature, 2017Co-Authors: Riccardo Mezzadra, Evert De Vries, Meike E.w. Logtenberg, Maarten Slagter, Elisa A. Rozeman, Ingrid Hofland, Wei Wu, Raquel Gomezeerland, Annegien Broeks, Hugo M HorlingsAbstract:The clinical benefit for patients with diverse types of metastatic cancers that has been observed upon blockade of the interaction between PD-1 and PD-L1 has highlighted the importance of this inhibitory axis in the suppression of tumour-specific T-cell responses. Notwithstanding the key role of PD-L1 expression by cells within the tumour micro-environment, our understanding of the regulation of the PD-L1 Protein is limited. Here we identify, using a haploid genetic screen, CMTM6, a type-3 transmembrane Protein of previously unknown function, as a regulator of the PD-L1 Protein. Interference with CMTM6 expression results in impaired PD-L1 Protein expression in all human tumour cell types tested and in primary human dendritic cells. Furthermore, through both a haploid genetic modifier screen in CMTM6-deficient cells and genetic complementation experiments, we demonstrate that this function is shared by its closest family member, CMTM4, but not by any of the other CMTM members tested. Notably, CMTM6 increases the PD-L1 Protein pool without affecting PD-L1 (also known as CD274) transcription levels. Rather, we demonstrate that CMTM6 is present at the cell surface, associates with the PD-L1 Protein, reduces its ubiquitination and increases PD-L1 Protein half-life. Consistent with its role in PD-L1 Protein regulation, CMTM6 enhances the ability of PD-L1-expressing tumour cells to inhibit T cells. Collectively, our data reveal that PD-L1 relies on CMTM6/4 to efficiently carry out its inhibitory function, and suggest potential new avenues to block this pathway.
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Identification of CMTM6 and CMTM4 as PD-L1 Protein regulators
Nature, 2017Co-Authors: Riccardo Mezzadra, Lucas T. Jae, Raquel Gomez-eerland, Evert De Vries, Meike E.w. Logtenberg, Maarten Slagter, Elisa A. Rozeman, Chong Sun, Wei Wu, Ingrid HoflandAbstract:CMTM6 and CMTM4 bind to and stabilize the inhibitory receptor PD-L1 and regulate PD-L1 levels at the surface of human tumour and immune cells.
Minmin Song - One of the best experts on this subject based on the ideXlab platform.
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pten loss increases pd L1 Protein expression and affects the correlation between pd L1 expression and clinical parameters in colorectal cancer
PLOS ONE, 2013Co-Authors: Minmin Song, Defeng Chen, Biyan Lu, Lanlan Huang, Christopher L. Timmons, Chenliang Wang, Jun Hu, Xiaoyan Wang, J. Zhang, Xiaojian WuAbstract:Background Programmed death ligand-1 (PD-L1) has been identified as a factor associated with poor prognosis in a range of cancers, and was reported to be mainly induced by PTEN loss in gliomas. However, the clinical effect of PD-L1 and its regulation by PTEN has not yet been determined in colorectal cancer (CRC). In the present study, we verified the regulation of PTEN on PD-L1 and further determined the effect of PTEN on the correlation between PD-L1 expression and clinical parameters in CRC. Methods/Results RNA interference approach was used to down-regulate PTEN expression in SW480, SW620 and HCT116 cells. It was showed that PD-L1 Protein, but not mRNA, was significantly increased in cells transfected with siRNA PTEN compared with the negative control. Moreover, the capacity of PTEN to regulate PD-L1 expression was not obviously affected by IFN-γ, the main inducer of PD-L1. Tissue microarray immunohistochemistry was used to detect PD-L1 and PTEN in 404 CRC patient samples. Overexpression of PD-L1 was significantly correlated with distant metastasis (P<0.001), TNM stage (P<0.01), metastatic progression (P<0.01) and PTEN expression (P<0.001). Univariate analysis revealed that patients with high PD-L1 expression had a poor overall survival (P<0.001). However, multivariate analysis did not support PD-L1 as an independent prognostic factor (P = 0.548). Univariate (P<0.001) and multivariate survival (P<0.001) analysis of 310 located CRC patients revealed that high level of PD-L1 expression was associated with increased risks of metastatic progression. Furthermore, the clinical effect of PD-L1 on CRC was not statistically significant in a subset of 39 patients with no PTEN expression (distant metastasis: P = 0.102; TNM stage: P = 0.634, overall survival: P = 0.482). Conclusions PD-L1 can be used to identify CRC patients with high risk of metastasis and poor prognosis. This clinical manifestation may be partly associated with PTEN expression.
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PTEN Loss Increases PD-L1 Protein Expression and Affects the Correlation between PD-L1 Expression and Clinical Parameters in Colorectal Cancer
PLoS ONE, 2013Co-Authors: Minmin Song, Defeng Chen, Biyan Lu, Lanlan Huang, Christopher L. Timmons, Junxiao Zhang, Chenliang Wang, Jun Hu, Xiaoyan Wang, Bindong LiuAbstract:BackgroundProgrammed death ligand-1 (PD-L1) has been identified as a factor associated with poor prognosis in a range of cancers, and was reported to be mainly induced by PTEN loss in gliomas. However, the clinical effect of PD-L1 and its regulation by PTEN has not yet been determined in colorectal cancer (CRC). In the present study, we verified the regulation of PTEN on PD-L1 and further determined the effect of PTEN on the correlation between PD-L1 expression and clinical parameters in CRC.Methods/ResultsRNA interference approach was used to down-regulate PTEN expression in SW480, SW620 and HCT116 cells. It was showed that PD-L1 Protein, but not mRNA, was significantly increased in cells transfected with siRNA PTEN compared with the negative control. Moreover, the capacity of PTEN to regulate PD-L1 expression was not obviously affected by IFN-γ, the main inducer of PD-L1. Tissue microarray immunohistochemistry was used to detect PD-L1 and PTEN in 404 CRC patient samples. Overexpression of PD-L1 was significantly correlated with distant metastasis (P
David L Rimm - One of the best experts on this subject based on the ideXlab platform.
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clinical significance of pd L1 Protein expression on tumor associated macrophages in lung cancer
Journal for ImmunoTherapy of Cancer, 2015Co-Authors: Kurt A Schalper, Joseph Mclaughlin, Daniel E Carvajalhausdorf, Vamsidhar Velcheti, Roy S Herbst, Lieping Chen, Miguel F Sanmamed, David L RimmAbstract:Tumor PD-L1 expression is associated with increased tumor-infiltrating lymphocytes (TILs) in diverse solid tumors, including lung cancer. In addition, PD-L1 upregulation in tumor and/or stromal immune cells has been associated with increased clinical benefit to PD-1/PD-L1 axis blockers. The significance of PD-L1 expression in different immune cell subpopulations at the tumor microenvironment remains poorly understood. Here, we measured PD-L1 Protein specifically in tumor-associated macrophages using objective methods and analyzed its clinical significance in human lung cancer.
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domain specific pd L1 Protein measurement in non small cell lung cancer nsclc
Journal of Clinical Oncology, 2014Co-Authors: Joseph Mclaughlin, Kurt A Schalper, Daniel E Carvajalhausdorf, Vamsidhar Velcheti, Herbert Haack, Matthew Ren Silver, Sarah B Goldberg, Roy S Herbst, David L RimmAbstract:8064 Background: PD-L1 Protein expression is being explored as a companion predictive test for anti-PD-1 therapies. Studies from our group, however, reveal limitations of available antibodies and i...
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Abstract P2-10-02: PD-L1 Protein expression is a prognostic biomarker in breast cancer
Cancer Research, 2013Co-Authors: Hallie Wimberly, Kurt A Schalper, Vamsidhar Velcheti, Lieping Chen, Lajos Pusztai, David L RimmAbstract:BACKGROUND: Programmed death ligand 1 (PD-L1) and its receptor, PD1, are involved in limiting immune response. In the context of cancer, tumor cells expressing PD-L1 can suppress the immune response of PD1-expressing tumor infiltrating lymphocytes (TILs). Disruption of this pathway with antibodies to either the ligand or the receptor has shown promise in the treatment of non small cell lung cancer, melanoma and renal cell cancer. Here we investigate the pathway in breast cancer. METHODS: PD-L1 Protein expression was assessed on two Yale TMA breast cancer cohorts with two-fold redundancy by quantitative immunofluorescence (QIF) using AQUA technology. Cohort 1 (YTMA201) consists of 400 patients with has extensive follow-up and adjuvant treatment information. Cohort 2 (YTMA128) consists of 245 patients with limited follow-up and no treatment information. The PD-L1 antibody (Lieping Chen, clone 5H1) has been previously validated for specificity and reproducibility using transfected cell models. TILs were assessed by a pathologist for each cohort using a score from 0-3 based on the amount of TILs within the spot. AQUA scores for PD-L1 were used as a continuous variable and also cut at the median for outcome analysis. RESULTS: PD-L1 Protein is positively correlated with TILs (p CONCLUSIONS: PD-L1 expression in breast cancer is positively associated with TILs and inversely associated with estrogen receptor status on two independent breast cancer cohorts. PD-L1 Protein expression shows prognostic value in breast cancer patients, particularly the ER positive subset of patients. Further assessment of PD-1 axis marker expression may be valuable as the associated therapeutics are being tested in breast cancer patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-10-02.
Wei Wu - One of the best experts on this subject based on the ideXlab platform.
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identification of cmtm6 and cmtm4 as pd L1 Protein regulators
Nature, 2017Co-Authors: Riccardo Mezzadra, Evert De Vries, Meike E.w. Logtenberg, Maarten Slagter, Elisa A. Rozeman, Ingrid Hofland, Wei Wu, Raquel Gomezeerland, Annegien Broeks, Hugo M HorlingsAbstract:The clinical benefit for patients with diverse types of metastatic cancers that has been observed upon blockade of the interaction between PD-1 and PD-L1 has highlighted the importance of this inhibitory axis in the suppression of tumour-specific T-cell responses. Notwithstanding the key role of PD-L1 expression by cells within the tumour micro-environment, our understanding of the regulation of the PD-L1 Protein is limited. Here we identify, using a haploid genetic screen, CMTM6, a type-3 transmembrane Protein of previously unknown function, as a regulator of the PD-L1 Protein. Interference with CMTM6 expression results in impaired PD-L1 Protein expression in all human tumour cell types tested and in primary human dendritic cells. Furthermore, through both a haploid genetic modifier screen in CMTM6-deficient cells and genetic complementation experiments, we demonstrate that this function is shared by its closest family member, CMTM4, but not by any of the other CMTM members tested. Notably, CMTM6 increases the PD-L1 Protein pool without affecting PD-L1 (also known as CD274) transcription levels. Rather, we demonstrate that CMTM6 is present at the cell surface, associates with the PD-L1 Protein, reduces its ubiquitination and increases PD-L1 Protein half-life. Consistent with its role in PD-L1 Protein regulation, CMTM6 enhances the ability of PD-L1-expressing tumour cells to inhibit T cells. Collectively, our data reveal that PD-L1 relies on CMTM6/4 to efficiently carry out its inhibitory function, and suggest potential new avenues to block this pathway.
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Abstract LB-291: Identification of CMTM6 and CMTM4 as PD-L1 Protein regulators
Cancer Research, 2017Co-Authors: Riccardo Mezzadra, Raquel Gomez-eerland, Evert De Vries, Wei Wu, Yanling Xiao, Albert J. R. Heck, Jannie Borst, Thijn R. BrummelkampAbstract:The clinical benefit in patients with diverse types of metastatic cancers that is observed upon blockade of the PD-1 - PD-L1 interaction has highlighted the importance of this inhibitory axis in the suppression of human tumor-specific T cell responses. In spite of the key role of PD-L1 expression by cells within the tumor microenvironment, our understanding of the regulation of the PD-L1 Protein is limited. Using a haploid genetic screen, we here identify CMTM6, a poorly described type 3 transmembrane Protein of previously unknown function, as a regulator of the PD-L1 Protein. Interference with CMTM6 expression results in impaired PD-L1 Protein expression in all tumor cell types tested and also in primary human dendritic cells. Furthermore, through both a haploid genetic modifier screen in CMTM6 deficient cells and genetic complementation experiments, we demonstrate that this function is shared by its closest family member CMTM4, but not by all other CMTM members tested. Notably, CMTM6 increases the PD-L1 Protein pool without affecting PD-L1 transcript levels. Rather, we demonstrate that CMTM6 is present at the cell surface, associates with PD-L1 Protein, and increases PD-L1 Protein half-life. Consistent with this role, T cell inhibitory capacity of PD-L1 expressing tumor cells is enhanced by CMTM6. Collectively, our data reveal that PD-L1 relies on CMTM6/4 to efficiently carry out its inhibitory function, and suggest potential new avenues to block this pathway. [C.S., R.M., and L.T.J. contributed equally to this work. T.R.B. and T.N.M.S. are both corresponding authors.] Citation Format: Chong Sun, Riccardo Mezzadra, Lucas T. Jae, Raquel Gomez-Eerland, Evert de Vries, Wei Wu, Yanling Xiao, Albert J. Heck, Jannie Borst, Thijn R. Brummelkamp, Ton N. Schumacher. Identification of CMTM6 and CMTM4 as PD-L1 Protein regulators [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-291. doi:10.1158/1538-7445.AM2017-LB-291
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Identification of CMTM6 and CMTM4 as PD-L1 Protein regulators
Nature, 2017Co-Authors: Riccardo Mezzadra, Lucas T. Jae, Raquel Gomez-eerland, Evert De Vries, Meike E.w. Logtenberg, Maarten Slagter, Elisa A. Rozeman, Chong Sun, Wei Wu, Ingrid HoflandAbstract:CMTM6 and CMTM4 bind to and stabilize the inhibitory receptor PD-L1 and regulate PD-L1 levels at the surface of human tumour and immune cells.
