Biology subjects

Scharer, C.

Publications and source records attributed to Scharer, C..

4 recordsLinked to original sources

bioRxiv2026

Jump-starting the T cell response in established tumors

Checkpoint blockade only works in 10-20% of patients. Consequently, investigators are testing checkpoint inhibitors in combination with drugs like the class I histone deacetylase inhibitor, entinostat (ENT). Unfortunately, the combination of ENT and checkpoint blockade fared poorly in patients with breast or ovarian cancer, despite promising pre-clinical results. Here we show that ENT enhances CD8+ T cell responses by maintaining a progenitor-like population of CD8+ T cells that supplies activated effector T cells to tumors for prolonged periods. Surprisingly, the anti-tumor effects of ENT are only experienced when delivered during a narrow window that occurs after T cell activation and before T cell exhaustion--a window that is likely closed in most patients. However, by first "jump-starting" the T cell response using an oncolytic virus, the anti-tumor activity of ENT and PD1 blockade is restored. These data establish a general paradigm, independent of tumor type, to rationally manipulate anti-tumor immunity.

immunology↗

bioRxiv2025

Xist RNA Dependent and Independent Mechanisms Regulate Dynamic X Chromosome Inactivation in B Lymphocytes

X-Chromosome Inactivation (XCI) involves epigenetic pathways to equalize X-linked gene expression between female and male mammals. XCI is dynamic in female B cells, as cytological enrichment of Xist RNA and heterochromatic marks on the inactive X-chromosome (Xi) are absent in naive B cells yet return following mitogenic stimulation. Here, we asked whether any heterochromatic histone marks are present on the Xi in naive B cells, and whether Xist RNA is required for their deposition and retention following stimulation. We find that the Xi in naive B cells is depleted for H2AK119Ub and H3K9me3 but enriched for DNA methylation and H3K27me3, which maintain an Xist RNA-dependent epigenetic memory of XCI. Upon stimulation, Xist-independent H3K27me3 and Xist-dependent H2AK119Ub modifications accumulate across the Xi with temporal and spatial specificity. Our findings reveal the importance of Xist RNA, H3K27me3, and H2AK119Ub marks for the epigenetic integrity of X-linked genes across the Xi following female B cell stimulation.

genetics↗

bioRxiv2023

Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness

The cumulative effects of T cell receptor (TCR) signal transduction over extended periods of time influences T cell biology, such as the positive selection of immature thymocytes or the proliferative responses of naive T cells. Naive T cells experience recurrent TCR signaling in response to self-antigens in the steady state. However, how these signals influence the responsiveness of naive CD8+ T cells to subsequent agonist TCR stimulation remains incompletely understood. We investigated how naive CD8+ T cells that experienced relatively low or high levels of TCR signaling in response to self-antigens respond to stimulation with foreign antigens. A transcriptional reporter of Nr4a1 (Nur77-GFP) revealed substantial heterogeneity of the amount of TCR signaling naive CD8+ T cells accumulate in the steady state. Nur77-GFPHI cells exhibited diminished T cell activation and secretion of IFN{gamma} and IL-2 relative to Nur77-GFPLO cells in response to agonist TCR stimulation. Differential gene expression analyses revealed upregulation of genes associated with acutely stimulated T cells in Nur77-GFPHI cells but also increased expression of negative regulators such as the phosphatase Sts1. Responsiveness of Nur77-GFPHI cells to TCR stimulation was partially restored at the level of IFN{gamma} secretion by deficiency of Sts1 or the ubiquitin ligase Cbl-b. Our data suggest that extensive accumulation of TCR signaling during steady state conditions induces a recalibration of the responsiveness of naive CD8+ T cells through gene expression changes and negative regulation, at least in part, dependent on Sts1 and Cbl-b. This cell-intrinsic negative feedback loop may allow the immune system to limit the autoreactive potential of highly self-reactive naive CD8+ T cells.

immunology↗

bioRxiv2021

Maturation of Human Long-lived Plasma Cells Results in Resistance to Apoptosis by Transcriptional and Epigenetic Regulation

Antibody secreting cells (ASC) circulate after vaccination and migrate to the bone marrow (BM) where a subset known as long-lived plasma cells (LLPC) persist and secrete antibodies for a lifetime. The mechanisms of how circulating ASC become LLPC are not well elucidated. Here, we show that human blood ASCs have distinct morphology, transcriptomes, and epigenetics compared to BM LLPC. LLPC acquire transcriptional and epigenetic changes in the apoptosis pathway to support their survival. Upregulation of pro-survival gene expression accompanies downregulation of pro-apoptotic gene expression in LLPC. While pro-apoptotic gene loci are less accessible, pro-survival gene loci are not always accompanied by accessibility changes. Importantly, we show similar LLPC morphological and transcriptional maturation of blood ASC in response to the novel in vitro BM mimetic. In all, our study demonstrates that blood ASC in the BM microniche must undergo morphological and molecular changes to mature into apoptotic-resistant LLPC.

immunology↗