Yee, C. | bioRxiv Science

bioRxiv2019

The Role of CD147 in Leukocyte Aggregation in Liver Injury

BackgroundChronic inflammation is the driver of liver injury resulting in progressive fibrosis and eventual cirrhosis. The consequences include both liver failure and liver cancer. We have previously described increased expression of the highly multifunctional glycoprotein CD147 in liver injury. This work describes a novel role of CD147 in liver inflammation and the importance of leukocyte aggregates in determining the extent of liver injury.\n\nMethodsNon-diseased, progressive injury and cirrhotic liver from humans and mice were examined using mAb targeting CD147. Inflammatory cell subsets were assessed by multicolor flow cytometry.\n\nResultsIn liver injury, we observe abundant intrahepatic leukocyte clusters defined as [≥]5 adjacent CD45+ cells which we have labelled \"leukocyte aggregates\". We have shown that these leukocyte aggregates are significant in determining the extent of liver injury. If CD147 is blocked in vivo, these leukocyte aggregates diminish in size and number together with a marked significant reduction in liver injury including fibrosis. This accompanied by no change in overall intrahepatic leukocyte numbers. Further, blocking aggregation formation occurs prior to an appreciable increase in inflammatory markers or fibrosis. Additionally, there were no observed, \"off-target\" or unpredicted effects in targeting CD147.\n\nConclusionCD147 mediates leukocyte aggregation which is associated with the development of liver injury. This is not a secondary effect, but a cause of injury as aggregate formation proceeds other markers of injury. Leukocyte aggregation has been previously described in inflammation dating back over many decades but till now been shown to determine the extent of injury.

immunology↗

bioRxiv2019

Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma

CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6/HDAC3 onco-repressor complex. Accordingly, we show that HDAC3 selective inhibitors fully reverse CREBBP mutant aberrant epigenetic programming resulting in: a) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and b) restoration of immune surveillance due to induction of BCL6 repressed IFN pathway and antigen presentation genes. By reactivating these genes, exposure to HDAC3-i restored the ability of tumor infiltrating lymphocytes to kill DLBCL cells in an MHC II and MHC I dependent manner. Hence HDAC3-i represent a novel mechanism-based immune-epigenetic therapy for CREBBP mutant lymphomas. STATEMENT OF SIGNIFICANCEWe have leveraged the molecular characterization of different types of CREBBP mutations to define a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in CREBBP mutant cells in tandem with promoting anti-tumor immunity.

cancer biology↗