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Plasminogen activator inhibitor-1 promotes immunosuppression in cancer by modulating immune component of tumor microenvironment.

In Annals of Oncology
By: Yadav P.
Contributor(s): Kumar N | Kumar A | Kapoor A | Beniwal S | Kalwar A.
Material type: materialTypeLabelArticlePublisher: 2018Description: .Subject(s): Plasminogen activator | Immunosuppression in cancer | Tumor microenvironment In: Annals of OncologySummary: Background: Plasminogen activator inhibitor-1 (PAI-1) is corelated with inflammation and tumorigenesis. We investigated the role of PAI-1 in tumor regulating immune component of tumor microenvironment. Methods: Protein expression data proteins and phosphoproteins, tumor infiltrating immune cells with relative fraction of immune cell types and major clinical outcome endpoints were obtained from The Cancer Genome Atlas project. A statistical correlation analysis was performed between the expression and distribution of PAI-1, immune checkpoint expression, tumor infiltrating immune cells fraction and their distribution in each tumor. We used Cox proportional hazards model to evaluate the association of PAI-1 with clinical survival outcomes. Results: The expression and distribution patterns of PAI-1 was measured in 7858 samples from 32 cancer type. PAI-1 had an enrichment in the squamous cancers. Increased expression of PAI-1 was associated with higher tumor stage and grade. Analyses of the tumor microenvironment revealed unanticipated correlation of PAI-1 with immune checkpoint expression and infiltrating immune cells. PAI-1 expression was tightly correlated to TGF-beta response (corr=0.40; p < 0.01), tumor leucocyte fraction (corr=0.33; p < 0.01) and PD-L1 expression (corr=0.29; p < 0.01). PAI-1 was positively corelates with intra-tumor heterogeneity (p < 0.01), proliferation(p < 0.01), stroma fraction (p < 0.01) and macrophages (p < 0.01). PAI-1 was also negatively correlated with lymphocyte fraction, activate CD4 cells, T cells (FH, gamma-delta and CD8). These correlations were also found with individual cancer type. PAI-1 was associated with poor Overall survival (Hazards ratio (HR)= 1.4; p < 0.01), Progression free interval (HR = 1.3; p < 0.01), disease free interval (HR = 1.26; p < 0.01) and disease specific survival (HR = 1.42; p < 0.01). PAI-1 was also associated with poor clinical outcomes in individual cancer type. Legal entity responsible for the study: Narender Kumar. Conclusions: PAI-1 is correlated with PD-L1 and influences the tumor progression by modulating tumor microenvironment. PAI-1 might be valuable target indicating opportunities for personalised combination therapy of cancer.
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Articles Articles Tata Memorial Hospital
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Abstract Book of Molecular Analysis for Personalised Therapy (MAP) 2018 14–15 September, Paris, France

Background: Plasminogen activator inhibitor-1 (PAI-1) is corelated with inflammation and tumorigenesis. We investigated the role of PAI-1 in tumor regulating immune component of tumor microenvironment.

Methods: Protein expression data proteins and phosphoproteins, tumor infiltrating immune cells with relative fraction of immune cell types and major clinical outcome endpoints were obtained from The Cancer Genome Atlas project. A statistical correlation analysis was performed between the expression and distribution of PAI-1, immune checkpoint expression, tumor infiltrating immune cells fraction and their distribution in each tumor. We used Cox proportional hazards model to evaluate the association of PAI-1 with clinical survival outcomes.

Results: The expression and distribution patterns of PAI-1 was measured in 7858 samples from 32 cancer type. PAI-1 had an enrichment in the squamous cancers. Increased expression of PAI-1 was associated with higher tumor stage and grade. Analyses of the tumor microenvironment revealed unanticipated correlation of PAI-1 with immune checkpoint expression and infiltrating immune cells. PAI-1 expression was tightly correlated to TGF-beta response (corr=0.40; p < 0.01), tumor leucocyte fraction (corr=0.33; p < 0.01) and PD-L1 expression (corr=0.29; p < 0.01). PAI-1 was positively corelates with intra-tumor heterogeneity (p < 0.01), proliferation(p < 0.01), stroma fraction (p < 0.01) and macrophages (p < 0.01). PAI-1 was also negatively correlated with lymphocyte fraction, activate CD4 cells, T cells (FH, gamma-delta and CD8). These correlations were also found with individual cancer type. PAI-1 was associated with poor Overall survival (Hazards ratio (HR)= 1.4; p < 0.01), Progression free interval (HR = 1.3; p < 0.01), disease free interval (HR = 1.26; p < 0.01) and disease specific survival (HR = 1.42; p < 0.01). PAI-1 was also associated with poor clinical outcomes in individual cancer type.

Legal entity responsible for the study: Narender Kumar.

Conclusions: PAI-1 is correlated with PD-L1 and influences the tumor progression by modulating tumor microenvironment. PAI-1 might be valuable target indicating opportunities for personalised combination therapy of cancer.

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