Biology subjects

Holler, E.

Publications and source records attributed to Holler, E..

5 recordsLinked to original sources

bioRxiv2026

Timed STING Inhibition Mitigates Gastrointestinal GvHD While Preserving Graft-versus-Leukemia Activity After Allo-HSCT

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative for hematological malignancies but limited by graft-versus-host disease (GvHD), in which donor T cells damage host tissues. Current prophylaxis broadly suppresses donor immunity, often compromising the beneficial graft-versus-leukemia (GvL) response, highlighting the need for strategies that uncouple GvHD from GvL. The cGAS-STING pathway can be strongly activated during conditioning-induced tissue damage and represents a potential therapeutic target. However, its context-dependent roles in inflammation and homeostasis have constrained its clinical translation. Here, we show that "timed" administration of the covalent STING inhibitor H151 before conditioning reduced GvHD-associated mortality without impairing GvL in murine allo-BMT models. Donor T cell activation and effector function were preserved, indicating that the protective effect operates at the level of GvHD target tissues rather than through systemic immunosuppression. Timed STING inhibition protected the intestinal epithelium by limiting apoptosis, preserving intestinal stem cell function, and sustaining metabolic fitness during conditioning-induced injury, independently of type I interferon (IFN-I) signaling. In allo-HSCT patients, low intestinal STING expression is associated with reduced transplant-related mortality. Together, these findings identify timed STING inhibition as a tissue-protective prophylactic strategy that could be incorporated into existing conditioning regimens to enhance efficacy while minimizing toxicity.

immunology↗

bioRxiv2025

A microbial metabolite protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration

Changes in the intestinal microbiome and microbiota-derived metabolites predict clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that desaminotyrosine (DAT), a product of bacterial flavonoid metabolism, correlates with improved overall survival and reduced relapse rates in allo-HSCT patients. In preclinical mouse models, treatment with synthetic DAT prevents graft-versus-host disease by protecting the intestinal barrier and promoting intestinal regeneration and contributes to graft-vs.-leukemia responses. DATs beneficial effects on intestinal regeneration remain effective despite broad-spectrum antibiotics-induced dysbiosis, also when administered by fecal microbiota transfer with flavonoid-degrading F. plautii. Mechanistically, DAT promotes mTORC1-dependent activation and proliferation of intestinal stem cells, with concomitant engagement of the innate immune receptor STING required to mitigate metabolic stress and maintain an undifferentiated stem cell state independently of type-I interferon responses. Additionally, DAT can skew T cells towards an effector phenotype to modulate graft-versus-leukemia responses. Our data uncover DATs dual, tissue- and immune-modulating properties and underscore its potential in precision microbiome-based therapies to improve tissue regeneration and minimize immune-mediated side effects.

immunology↗

bioRxiv2025

Antibody-Free Immunopeptide Nano-Conjugates for Brain-Targeted Drug Delivery in Glioblastoma Multiforme

Glioblastoma Multiforme (GBM) represents a significant clinical challenge amongst central nervous system (CNS) tumors, with a dismal mean survival rate of less than 8 months, a statistic that has remained largely unchanged for decades (National Brain Society, 2022). The specialized intricate anatomical features of the brain, notably the blood-brain barrier (BBB), pose significant challenges to effective therapeutic interventions, limiting the potential reach of modern advancements in immunotherapy to impact these types of tumors. This study introduces an innovative, actively targeted immunotherapeutic nanoconjugate (P12/AP-2/NCs) designed to serve as an immunotherapeutic agent capable of traversing the BBB via LRP-1 receptor-mediated transcytosis. P12/AP-2/NCs exert its immune-modulating effects by inhibiting the PD-1/PD-L1 axis through a small-size PD-L1/ PD-L2 antagonist peptide Aurigene NP-12 (P12). P12/AP-2/NCs are synthesized from completely biodegradable, functionalized high molecular weight {beta}-poly(L-malic acid) (PMLA) polymer, conjugated with P12 and Angiopep-2 (AP2) to yield P12/AP-2/NCs. Evaluating nanoconjugates for BBB permeability and 3-D tumor model efficacy using an in vitro BBB-Transwell spheroid based model demonstrating successful crossing of the BBB and internalization in brain 3D tumor environments. In addition, the nanoconjugate mediated T cells cytotoxicity on 3D tumor region death in a U87 GBM 3-D spheroid model. AP2/P12/NCs is selectively inhibited in PD1/PDL1 interaction on T cells and tumor site, increasing inflammatory cytokine secretion and T cell proliferation. In an in-vivo murine brain environment, rhodamine fluorophore-labeled AP2/P12/NCs displayed significantly increased accumulation in the brain during 2-6 h time intervals post-injection with a prolonged bioavailability over unconjugated peptides. AP2/P12/NCs demonstrated a safety profile at both low and high doses based on major organ histopathology evaluations. Our findings introduce a novel, programmable nanoconjugate platform capable of penetrating the BBB for directed delivery of small peptides and significant immune environment modulation without utilizing antibodies, offering promise for treating challenging brain diseases like glioblastoma multiforme and beyond.

immunology↗

bioRxiv2024

Tissue-adapted Tregs harness inflammatory signals to promote intestinal repair from therapy-related injury

Intestinal stem cells (ISC) promote tissue repair after genotoxic or immune-mediated injury. However, ISCs are particularly sensitive to various stressors and primary targets of overwhelming immune responses such as interferon-{gamma} (IFN{gamma})-mediated killing. In mouse models of gut damage and biopsies from patients having undergone allo-hematopoietic stem cell transplantation, we observed IFNy expression by intestinal Treg cells. Treg cells leverage combined IFN{gamma} and interleukin 10 (IL-10) stimulation of ISCs to nurture the growth of intestinal organoids through the activation of the mTORC1 and Myc pathways. Similarly, Treg cells or the combined addition of recombinant IFN{gamma} and IL-10 promote the regeneration of organoids after irradiation. Exposure of organoids to Wnt- or EGF-free culture conditions revealed distinct growth factor-like properties of IFN{gamma} and IL-10. While IFN{gamma} induced epithelial proliferation and differentiation, combined addition of IFN{gamma} and IL-10 led to balanced proliferation, ensuring ISC maintenance. Our results uncover a context-dependent role of inflammatory signaling in ISC, through which Treg cells promote epithelial repair.

immunology↗

bioRxiv2018

Nano immunoconjugates crossing blood-brain barrier activate local brain tumor immune system for glioma treatment

Treatment of brain gliomas with checkpoint inhibitor antibodies to cytotoxic T-lymphocyte-associated antigen 4 (a-CTLA-4) and programmed cell death-1 (a-PD-1) was largely unsuccessful due to their inability to cross the blood-brain barrier (BBB). We describe a new generation of nano immunoconjugates (NICs) developed on natural biopolymer scaffold, poly({beta}-L-malic acid), with covalently attached a-CTLA-4 and/or a-PD-1 for delivery across the BBB and activation of local brain anti-tumor immune response in glioma-bearing mice. NIC treatment of mice bearing intracranial GL261 glioblastoma (GBM) resulted in an increase of CD8+ T-cells with a decrease of T regulatory cells (Tregs) in the brain tumor area. Survival of GBM-bearing mice treated with combination of NICs was significantly longer compared to animals treated by single checkpoint inhibitor-bearing NICs or free a-CTLA-4 and a-PD-1. Our study demonstrates trans-BBB delivery of nanopolymer-conjugated checkpoint inhibitors as an effective treatment of GBM via activation of both systemic and local brain tumor immune response.

immunology↗