Project description:Transcriptome analysis was used to identify tumor-independent changes after treatment with mouse neutralizing PD-1 or PD-L1 antibodies.
Project description:BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We discovered that the maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and IFN-γ induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD1/PD-L1 axis by combining anti-PD1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncovers a novel interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provides novel insight into the transcriptional regulation of CD274.
Project description:BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We discovered that the maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and IFN-γ induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD1/PD-L1 axis by combining anti-PD1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncovers a novel interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provides novel insight into the transcriptional regulation of CD274.
Project description:BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We discovered that the maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and IFN-γ induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD1/PD-L1 axis by combining anti-PD1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncovers a novel interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provides novel insight into the transcriptional regulation of CD274.
Project description:Transcriptome analysis was used to identify tumor-independent changes after treatment with different tyrosine kinase inhibitors (TKIs).
Project description:we found that a proportion of human and murine brain tumor-initiating cells (BTICs) expressed programmed cell death protein (PD-1) in situ and in culture. PD-1 signaling through NF B promotes BTIC proliferation.
Project description:Anti-PD-1 immunotherapy has demonstrated significant anti-tumor efficacy in treating relapsed or refractory natural killer/T cell lymphoma (R/R NKTL). However, both intrinsic and acquired resistance remain a substantial challenge. DNA hypermethylation serves as a critical epigenetic modifier influencing anti-tumor immunity in NKTL. Here, we evaluate the efficacy and safety of combining DNA methyltransferase (DNMT) inhibitors with anti-PD-1 monoclonal antibody (mAb) as salvage therapy in 21 patients with R/R NKTL who had previously failed frontline immunotherapy. This combination therapy achieved an objective response rate (ORR) of 66.7% (14/21), with a complete response (CR) rate of 47.6% (10/21), and a 2-year overall survival (OS) rate of 50.2%. To investigate the mechanisms underlying the therapeutic efficacy of this combination, we established a preclinical xenograft model of acquired resistance to anti-PD-1 therapy. Our findings revealed that resistance to anti-PD-1 treatment was characterized by the absence of CD8+ T-cell infiltration and the inactivation of interferon pathways. In contrast, DNMT inhibitors restored CD8+ T-cell infiltration, and sensitized tumors to anti-PD-1 therapy. Mechanistically, DNMT inhibitors induced DNA demethylation of endogenous retroviral elements (ERVs), leading to the upregulation of endogenous nucleic acid expression and the activation of a viral mimicry response. This response subsequently triggered the type I interferon pathway, thereby enhancing anti-tumor immunity in both murine and human T-cell lymphoma models. Collectively, our study highlights the potential of DNMT inhibitors in restoring tumor sensitivity to anti-PD-1 therapy and provides compelling evidence for combining DNMT inhibitors with anti-PD-1 mAb as a promising therapeutic strategy for R/R NKTL.