BCL6-Mediated Silencing of PD-1 Ligands in Germinal Center B Cells Maintains Follicular T Cell Population

Peng, Cheng; Hu, Qianwen; Yang, Fang; Zhang, Heng; Li, Fubin; Huang, Chuanxin

doi:10.4049/jimmunol.1800876

Cited by 26 publications

(27 citation statements)

References 44 publications

(88 reference statements)

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“…We found evidence for adaptive immune suppression within our model systems, showing that HDAC3 inhibition leads to increased IFNγ production and the upregulation of PD-L1 expression. This is in line with recent observations that CD274 (encoding PD-L1) is a BCL6-supressed gene (45) and with a well-characterized role for PD-L1 as an IFNγ-responsive gene (44). In other cancers in which a florid antigen-driven immune response and concomitant adaptive immune suppression via PD-L1 exist within the tumor microenvironment, blockade of the PD-1 receptor is an effective therapeutic strategy (15,17).…”

Section: Discussionsupporting

confidence: 86%

Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma

et al. 2020

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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 reverse CREBBP-mutant aberrant epigenetic programming, resulting in: (i) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and (ii) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen-presenting genes. By reactivating these genes, exposure to HDAC3 inhibitors restored the ability of tumor-infi ltrating lymphocytes to kill DLBCL cells in an MHC class I and II-dependent manner, and synergized with PD-L1 blockade in a syngeneic model in vivo. Hence, HDAC3 inhibition represents a novel mechanism-based immune epigenetic therapy for CREBBP-mutant lymphomas. SIGNIFICANCE: We have leveraged the molecular characterization of different types of CREBBP mutations to defi ne a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in CREBBPmutant cells in tandem with promoting antitumor immunity.

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Section: Discussionsupporting

confidence: 86%

Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma

et al. 2020

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“…We found evidence for adaptive immune suppression within our model systems, showing that HDAC3 inhibition leads to increased IFN-γ production and the upregulation of PD-L1 expression. This is in line with recent observations that PD-L1 ( CD274 ) is a BCL6-supressed gene 41 , and a well-characterized role for PD-L1 as an IFN-γ-responsive gene 40 . In other cancers in which a florid antigen-driven immune response and concomitant adaptive immune suppression via PD-L1 exist within the tumor microenvironment, blockade of the PD-1 receptor is an effective therapeutic strategy 13,15 .…”

Section: Discussionsupporting

confidence: 91%

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

Mondello

Tadros

Teater

et al. 2019

Preprint

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45 46CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its 47 histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that 48 these two classes of mutations yield different degrees of disruption of the epigenome, 49 with HAT mutations being more severe and associated with inferior clinical outcome. 50 Genes perturbed by CREBBP mutation are direct targets of the BCL6/HDAC3 onco-51 repressor complex. Accordingly, we show that HDAC3 selective inhibitors fully reverse 52 CREBBP mutant aberrant epigenetic programming resulting in: a) growth inhibition of 53 lymphoma cells through induction of BCL6 target genes such as CDKN1A and b) 54 restoration of immune surveillance due to induction of BCL6 repressed IFN pathway and 55 antigen presentation genes. By reactivating these genes, exposure to HDAC3-i restored 56 the ability of tumor infiltrating lymphocytes to kill DLBCL cells in an MHC II and MHC I 57 dependent manner. Hence HDAC3-i represent a novel mechanism-based immune-58 epigenetic therapy for CREBBP mutant lymphomas. 59 60 61 62 We have leveraged the molecular characterization of different types of CREBBP 63 mutations to define a rational approach for targeting these mutations through selective 64 inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting 65 synthetic vulnerabilities in CREBBP mutant cells in tandem with promoting anti-tumor 66 immunity. 67 68 69 70 Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the two most 71 frequent subtypes of non-Hodgkin lymphoma. These diseases originate from germinal 72 center B (GCB)-cells; a stage of development that naturally allows for the proliferation 73 and affinity maturation of antigen-experienced B-cells to produce terminally-differentiated 74 memory B-cells or plasma cells. The germinal center (GC) reaction is regulated by B-cell-75 intrinsic activation and suppression of large sets of genes by master regulators such as 76 the BCL6 transcription factor 1 , and extrinsically via the interaction of GCB-cells with 77 follicular helper T (TFH)-cells and other immune cells within the GC 2 . The BCL6 78 transcription factor is critical for GCB-cell development and coordinately suppresses the 79 expression of large sets of genes by recruiting SMRT and NCOR co-repressor complexes 80 containing HDAC3 3 and tethering a non-canonical polycomb repressor 1-like complex in 81 cooperation with EZH2 4 . These genes are normally reactivated to drive GC exit and 82 terminal differentiation, but the epigenetic control of these dynamically-regulated GC 83 transcriptional programs is perturbed in DLBCL and FL via the downstream effects of 84 somatic mutation of chromatin modifying genes 5 (CMG). 85 86 STATEMENT OF SIGNIFICANCEThe second most frequently mutated CMG in both DLBCL and FL is the CREBBP gene, 87 which encodes a histone acetyltransferase that activates transcription via acetylation of 88 histone H3 lysine 27 (H3K27Ac) and other residues. We have previously fo...

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“…While the preceding data demonstrated that BCL6-deficient B cells do not form CD73+CD80+ MBCs, it was possible that we had only altered the phenotype of the MBCs, but not their function. For example, BCL6 can negatively regulate the expression of several molecules associated with the MBC phenotype including CD80 and PD-L2 (Niu et al, 2003;Peng et al, 2018).…”

Section: Bcl6-dependent Cd73+cd80+ Mbcs Are Required For Rapid Plasmamentioning

confidence: 99%

A continuum of CD4+ T cell “help” defines Memory B cell fate

Netland

et al. 2019

Preprint

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Humoral immunity depends upon the development of long-lived, antibodysecreting plasma cells and rapidly responsive memory B cells (MBCs). The differentiation of high affinity, class-switched MBCs after immunization is critically dependent upon BCL6 expression in germinal center (GC) B cells and CD4+ T follicular helper (Tfh) cells. It is less well understood how more recently described MBC subsets are generated, including the CD73+CD80+ IgM+ MBCs that initially form antibody-secreting effector cells in response to a secondary Plasmodium infection. Herein, we interrogated how BCL6 expression in both B and CD4+ T cells influenced the formation of heterogeneous Plasmodium-specific MBC populations. All Plasmodium-specific CD73+CD80+ MBCs required BCL6 expression for their formation, suggesting germinal center dependence. Further dissection of the CD4+ T and B cell interactions however revealed that somatically hypermutated CD73+CD80+ IgM+ MBCs can form not only in the absence of germinal centers, but also in the absence of CXCR5+ CD4+ Tfh cells.

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BCL6-Mediated Silencing of PD-1 Ligands in Germinal Center B Cells Maintains Follicular T Cell Population

Cited by 26 publications

References 44 publications

Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma

Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma

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

A continuum of CD4+ T cell “help” defines Memory B cell fate

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