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Hepatic Stellate Cells Directly Inhibit B Cells via Programmed Death-Ligand 1.

ABSTRACT: We demonstrated previously that mouse hepatic stellate cells (HSCs) suppress T cells via programmed death-ligand 1 (PD-L1), but it remains unknown whether they exert any effects on B cells, the other component of the adaptive immune system. In this study, we found that mouse HSCs directly inhibited B cells and that PD-L1 was also integrally involved. We found that HSCs inhibited the upregulation of activation markers on activated B cells, as well as the proliferation of activated B cells and their cytokine/Ig production in vitro, and that pharmaceutically or genetically blocking the interaction of PD-L1 with programmed cell death protein 1 impaired the ability of HSCs to inhibit B cells. To test the newly discovered B cell-inhibitory activity of HSCs in vivo, we developed a protocol of intrasplenic artery injection to directly deliver HSCs into the spleen. We found that local delivery of wild-type HSCs into the spleens of mice that had been immunized with 4-hydroxy-3-nitrophenylacetyl-Ficoll, a T cell-independent Ag, significantly suppressed Ag-specific IgM and IgG production in vivo, whereas splenic artery delivery of PD-L1-deficient HSCs failed to do so. In conclusion, in addition to inhibiting T cells, mouse HSCs concurrently inhibit B cells via PD-L1. This direct B cell-inhibitory activity of HSCs should contribute to the mechanism by which HSCs maintain the liver's immune homeostasis.

SUBMITTER: Li Y

PROVIDER: S-EPMC4784705 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Hepatic Stellate Cells Directly Inhibit B Cells via Programmed Death-Ligand 1.

Li Yan Y Lu Lina L Qian Shiguang S Fung John J JJ Lin Feng F

Journal of immunology (Baltimore, Md. : 1950) 20160111 4

We demonstrated previously that mouse hepatic stellate cells (HSCs) suppress T cells via programmed death-ligand 1 (PD-L1), but it remains unknown whether they exert any effects on B cells, the other component of the adaptive immune system. In this study, we found that mouse HSCs directly inhibited B cells and that PD-L1 was also integrally involved. We found that HSCs inhibited the upregulation of activation markers on activated B cells, as well as the proliferation of activated B cells and the ...[more]

PMID: 26755818

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Project description:Importance:Therapies to inhibit programmed cell death 1 and its ligand (anti-PD-1/PD-L1) provide significant survival benefits in many cancers, but the efficacy of these treatments varies considerably across different cancer types. Identifying the underlying variables associated with this cancer type-specific response remains an important open research challenge. Objective:To evaluate systematically a multitude of neoantigen-, checkpoint-, and immune response-related variables to determine the key variables that accurately predict the response to anti-PD-1/PD-L1 therapy across different cancer types. Design, Setting, and Participants:This analysis of a broad range of data used whole-exome and RNA sequencing of 7187 patients from the publicly available Cancer Genome Atlas and the objective response rate (ORR) data of 21 cancer types obtained from a collection of clinical trials. Thirty-six variables of 3 distinct classes considered were associated with (1) tumor neoantigens, (2) tumor microenvironment and inflammation, and (3) the checkpoint targets. The performance of each class of variables and their combinations in predicting the ORR to anti-PD-1/PD-L1 therapy was evaluated. Accuracy of predictions was quantified with Spearman correlation measured using a standard leave-one-out cross-validation, a statistical method of evaluating a statistical model by dividing data into 2 segments: one to train the model and the other to validate the model. Data were collected from October 19 through 31, 2018, and were analyzed from November 1 through December 14, 2018. Main Outcomes and Measures:Response to anti-PD-1/PD-1 therapy. Results:Among the 36 variables, estimated CD8+ T-cell abundance was the most predictive of the response to anti-PD-1/PD-L1 therapy across cancer types (Spearman R?=?0.72; P?<?2.3?×?10-4), followed by the tumor mutational burden (Spearman R?=?0.68; P?<?6.2?×?10-4), and the fraction of samples with high PD1 gene expression (Spearman R?=?0.68; P?<?6.9?×?10-4). Notably these top 3 variables cover the 3 classes considered, and their combination is highly correlated with response (Spearman R?=?0.90; P?<?4.1?×?10-8), explaining more than 80% of the ORR variance observed across different tumor types. Conclusions and Relevance:That we know of, this is the first systematic evaluation of the different variables associated with anti-PD-1/PD-L1 therapy response across different tumor types. The findings suggest that the 3 key variables can explain most of the observed cross-cancer response variability, but their relative explanatory roles may vary in specific cancer types.

Dataset Information

Hepatic Stellate Cells Directly Inhibit B Cells via Programmed Death-Ligand 1.

Publications

Hepatic Stellate Cells Directly Inhibit B Cells via Programmed Death-Ligand 1.

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