Project description:Targeting chromatin binding proteins and modifying enzymes can concomitantly affect tumor cell proliferation and survival, as well as enhance anti-tumor immunity and augment cancer immunotherapies. By screening a small molecule library of epigenetics-based therapeutics, BET bromodomain inhibitors (BETi) were identified as agents that sensitize tumor cells to the anti-tumor activity of CD8+ T-cells. BETi modulated tumor cells to be sensitized to the cytotoxic effects of the pro-inflammatory cytokine TNF. By preventing the recruitment of BRD4 to p65-bound cis-regulatory elements, BETi suppressed the induction of inflammatory gene expression, including the key NF-B target genes BIRC2 (cIAP1) and BIRC3 (cIAP2). Disruption of pro-survival NF-B signaling by BETi led to unrestrained TNF-mediated activation of the extrinsic apoptotic cascade and tumor cell death. Administration of BETi in combination with T-cell bispecific (TCB) antibodies increased bystander killing of tumor cells and enhanced tumor growth inhibition in vivo in a TNF-dependent manner. This novel epigenetic mechanism of immunomodulation may guide future use of BETi as adjuvants for immune oncology agents.
Project description:Targeting chromatin binding proteins and modifying enzymes can concomitantly affect tumor cell proliferation and survival, as well as enhance anti-tumor immunity and augment cancer immunotherapies. By screening a small molecule library of epigenetics-based therapeutics, BET bromodomain inhibitors (BETi) were identified as agents that sensitize tumor cells to the anti-tumor activity of CD8+ T-cells. BETi modulated tumor cells to be sensitized to the cytotoxic effects of the pro-inflammatory cytokine TNF. By preventing the recruitment of BRD4 to p65-bound cis-regulatory elements, BETi suppressed the induction of inflammatory gene expression, including the key NF-B target genes BIRC2 (cIAP1) and BIRC3 (cIAP2). Disruption of pro-survival NF-B signaling by BETi led to unrestrained TNF-mediated activation of the extrinsic apoptotic cascade and tumor cell death. Administration of BETi in combination with T-cell bispecific (TCB) antibodies increased bystander killing of tumor cells and enhanced tumor growth inhibition in vivo in a TNF-dependent manner. This novel epigenetic mechanism of immunomodulation may guide future use of BETi as adjuvants for immune oncology agents.
Project description:Frameshift insertion/deletions can produce highly immunogenic neoantigens; however, frameshift-derived transcripts are often degraded by the nonsense-mediated mRNA decay (NMD) pathway. Leveraging multiomics and checkpoint in-hibitor (CPI) response data from over 1,000 patients, we demonstrate that reduced expression or genetic loss of the NMD mediator SMG1 correlates with improved CPI responses. SMG1 inhibition ex vivo and in vivo activates and expands tumour-reactive lymphocytes and potentiates CPI responses. Mechanistically, SMG1 inhibi-tion stabilises frameshift-derived transcripts and increases the abundance and sur-face presentation of immunogenic neoantigens, shifting the neoepitope count from a low- to a high-tumour mutational burden (TMB)-like state without causing DNA damage. Co-culture of lymphocytes with tumour cells upon SMG1i induces antigen-dependent T cell activation and tumour cell killing. Our findings highlight SMG1 in-hibition as a promising immuno-oncology strategy to harness an untapped source of immunogenic neoantigens to enhance tumour immunogenicity and improve CPI efficacy, with broad applicability irrespective of TMB status.
