Biology subjects

Bernard, B.

Publications and source records attributed to Bernard, B..

3 recordsLinked to original sources

bioRxiv2025

A tailored in vivo CRISPR screen identifies BAP1 as a potent tumor suppressor of soft tissue sarcoma

Undifferentiated pleomorphic sarcoma (UPS) is one of the most common soft tissue sarcomas (STS) in adults. Despite decades of research, therapeutic advancements for STS, including UPS, have remained limited. The genetic complexity of UPS, characterized by the absence of recurrent driver oncogene mutations, has hindered the development of effective targeted therapies beyond conventional chemotherapy and immunotherapy. To address this challenge, we conducted a customized in vivo CRISPR/Cas9 screen in mice to systematically identify potential tumor suppressors involved in UPS development. Our screen revealed BRCA1-associated protein 1 (Bap1) as a potent tumor suppressor in STS. Using total RNA sequencing, multiplex immunohistochemistry, and flow cytometry, we found that Bap1-deficient mouse sarcomas exhibit significant immune suppression. Further analysis indicated that polo-like kinase 1 (Plk1) is essential for the survival of Bap1-deficient sarcomas. Treatment with volasertib, a Plk1 inhibitor, markedly inhibited tumor growth in both syngeneic and spontaneous mouse models of Bap1-loss sarcoma. In conclusion, our findings suggest that PLK1 inhibition, or combined with immunotherapy, may represent a promising targeted therapeutic strategy for tumors lacking BAP1.

cancer biology↗

bioRxiv2022

Epigenetic silencing by SMYD3 represses tumor intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck.

Cancers often display immune escape, but the mechanisms and potential for reversibility are incompletely understood. Epigenetic dysregulation has been implicated in the immune escape of various cancer types. We have identified the epigenetic modifier SET and MYND-domain containing protein 3 (SMYD3) as a mediator of immune escape in human papilloma virus (HPV)- negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor prognosis and low response to immunotherapy with pembrolizumab, a programmed-death-1 (PD-1) targeting antibody. SMYD3 loss increased the sensitivity of HNSCC cancer cells to IFN-{beta}, resulting in upregulation of type I IFN response and antigen presentation machinery genes. We found that SMYD3 regulates the transcription of Ubiquitin-Like PHD And RING Finger Domain- Containing Protein 1 (UHRF1), a key epigenetic reader of trimethylated lysine 9 on histone H3 (H3K9me3), which binds to H3K9me3-enriched promoters of key immune-related genes and silences their expression. SMYD3 further maintains the repression of immune-related genes through the deposition of H4K20me3 within the gene body regions of these genes. In an anti-PD-1 immune checkpoint resistant syngeneic mouse model of HPV-negative HNSCC, Smyd3 depletion induced influx of CD8+ T-cells, upregulated PD-L1 and MHC class I molecules, and increased sensitivity to anti-PD-1 therapy. SMYD3 overexpression was associated with decreased CD8 T-cell infiltration in tumor samples from patients with HPV-negative HNSCC, and was associated with poor response to pembrolizumab. Overall, these data highlight a previously unreported function of SMYD3 as a master epigenetic regulator of anti-tumor immune response in HPV-negative HNSCC and provide a rationale for translational approaches combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in this devastating disease.

cancer biology↗

bioRxiv2017

Cytomegalovirus infection is a risk factor for TB disease in Infants

Immune activation is associated with increased risk of tuberculosis (TB) disease in infants. We performed a case-control analysis to identify drivers of immune activation and disease risk. Among 49 infants who developed TB disease over the first two years of life, and 129 matched controls who remained healthy, we found the cytomegalovirus (CMV) stimulated IFN-{gamma} response at age 4-6 months to be associated with CD8+ T-cell activation (Spearmans rho, p=6x10-8). A CMV specific IFN-{gamma} response was also associated with increased risk of developing TB disease (Conditional Logistic Regression, p=0.043, OR 2.2, 95% CI 1.02-4.83), and shorter time to TB diagnosis (Log Rank Mantel-Cox p=0.037). CMV positive infants who developed TB disease had lower expression of natural killer cell associated gene signatures and a lower frequency of CD3-CD4-CD8-lymphocytes. We identified transcriptional signatures predictive of risk of TB disease among CMV ELISpot positive (AUROC 0.98, accuracy 92.57%) and negative (AUROC 0.9, accuracy 79.3%) infants; the CMV negative signature validated in an independent infant study (AUROC 0.71, accuracy 63.9%). Understanding and controlling the microbial drivers of T cell activation, such as CMV, could guide new strategies for prevention of TB disease in infants.

immunology↗