Biology subjects

Boss, J.

Publications and source records attributed to Boss, J..

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↗

bioRxiv2026

Ocrelizumab Modulates Both B and T Cell Immune Capacities in Multiple Sclerosis

To understand the molecular and cellular mechanisms beyond B-cell depletion with the anti-CD20 monoclonal antibody ocrelizumab, we used comprehensive muti-modal flow cytometry and functional assays in a prospective longitudinal multiple sclerosis (MS) cohort. Ocrelizumab depleted the vast majority of B cells and showed selective effects on different B cells subsets. Analysis of residual/replenished B cells revealed relative enrichment of regulatory B cells like CD27+CD43+ B1 and CD24hiCD38hi transitional B cells, and reduction of CD27+ memory B cell subsets and CD19+IgD+CD27-naive B cells at early time points (1-3 month) and before subsequent infusions at 4-7 months, 11-14 months, and >18 months. CD20+ T cells and peripheral helper T-cells (Tph) were also reduced. RNA sequencing analysis showed B1 cells have significantly higher expression of LGALS1, KCNN4, ITGB1, and IL2RB. Compared to transitional B cells, B1 cells also displayed significantly higher expression of tissue homing molecules ITGAX (CD11c), S100A4, ITGB1, and CXCR3. IL10 signaling pathway is increased in these B cells. Ex vivo B cell functional assays indicated the residual/replenishing B cells were anergic following ocrelizumab, with increased IL10/TNF and IL10/IL6 ratios under BCR stimulation. Ocrelizumab treatment may create a self-reinforcing regulatory circuit: the reduction of Tph cells could alleviate suppression of regulatory B cells, which subsequently expand and further promote regulatory T cell networks via IL2RB, LGALS1, and an increased IL-10 signaling pathway.

immunology↗

bioRxiv2021

Conserved epigenetic programming and enhanced heme metabolism drive memory B cell reactivation

Memory B cells (MBCs) have enhanced capabilities to differentiate to plasma cells and generate a rapid burst of antibodies upon secondary stimulation. To determine if MBCs harbor an epigenetic landscape that contributes to increased differentiation potential, we derived the chromatin accessibility and transcriptomes of influenza-specific IgM and IgG MBCs compared to naive cells. MBCs possessed an accessible chromatin architecture surrounding plasma cell specific genes, as well as altered expression of transcription factors and genes encoding cell cycle, chemotaxis, and signal transduction processes. Intriguingly, this MBC signature was conserved between humans and mice. MBCs of both species possessed a heightened heme signature compared to naive cells. Differentiation in the presence of hemin enhanced oxidative phosphorylation metabolism and MBC differentiation into antibody secreting plasma cells. Thus, these data define conserved MBC transcriptional and epigenetic signatures that include a central role for heme and multiple other pathways in augmenting MBC reactivation potential. Key PointsO_LIInfluenza-specific memory B cells have accessible chromatin structure. C_LIO_LIHuman and mouse memory B cells upregulate heme metabolic pathways. C_LIO_LIHeme enhances PC differentiation and augments mitochondrial metabolism in ex vivo. C_LI

immunology↗

bioRxiv2019

PD-1 expression during acute infection is repressed through 1 a LSD1- Blimp-1 axis

During prolonged exposure to antigens, such as chronic viral infections, sustained T cell receptor (TCR) signaling can result in T cell exhaustion mediated in part by expression of Programmed cell death-1 (PD-1) encoded by the Pdcd1 gene. Here, dynamic changes in histone H3K4 modifications at the Pdcd1 locus during ex vivo and in vivo activation of CD8 T cells, suggested a potential role for the histone H3 lysine 4 demethylase LSD1 in regulating PD-1 expression. CD8 T cells lacking LSD1 expressed higher levels of Pdcd1 mRNA following ex vivo stimulation, as well as increased surface levels of PD-1 during acute but not chronic infection with lymphocytic choriomeningitis virus (LCMV). Blimp-1, a known repressor of PD-1, recruited LSD1 to the Pdcd1 gene during acute but not chronic LCMV infection. Loss of DNA methylation at Pdcd1s promoter proximal regulatory regions is highly correlated with its expression. However, following acute LCMV infection where PD-1 expression levels return to near base line, LSD1-deficient CD8 T cells failed to remethylate the Pdcd1 locus to the levels of wild-type cells. Finally, in a murine melanoma model, the frequency of PD-1 expressing tumor infiltrating LSD1-deficient CD8 T cells was greater than wild-type. Thus, LSD1 is recruited to the Pdcd1 locus by Blimp-1, downregulates PD-1 expression by facilitating the removal of activating histone marks, and is important for remethylation of the locus. Together, these data provide insight into the complex regulatory mechanisms governing T cell immunity and the regulation of a critical T cell checkpoint gene.\n\nKey PointsO_LILSD1 suppress PD-1 expression following acute infection or transient induction.\nC_LIO_LIBlimp-1 binding to the Pdcd1 locus is required to recruit LSD1.\nC_LIO_LILSD1 is required to fully remethylate the PD-1 proximal promoter region.\nC_LI

immunology↗