Biology subjects

Goettert, S.

Publications and source records attributed to Goettert, S..

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↗

bioRxiv2026

Targeting ZC3H12C improves T cell persistence and antitumor function in adoptive T cell therapy

Adoptive T cell therapy (ACT) has achieved remarkable clinical responses in hematologic malignancies but remains limited by progressive T cell dysfunction under chronic antigen stimulation. Here, we identify ZC3H12C as a conserved feature of dysfunctional T cells and show that its disruption enhances the durability and antitumor activity of engineered T cells. By integrating single-cell chromatin accessibility and transcriptomic profiling of human tumor-infiltrating lymphocytes (TILs), we identified the ZC3H12C locus as selectively remodeled in exhausted T cells. ZC3H12C induction is largely absent across acute T cell activation contexts, indicating regulation that is specific to chronic antigen-driven dysfunction. Genetic disruption of ZC3H12C improves T cell expansion, cytotoxicity, and expression of effector molecules during repeated in vitro stimulation, translating into enhanced tumor control in vivo across both T cell receptor (TCR) and chimeric antigen receptor (CAR) T cell therapy platforms. Improved efficacy is observed in hematologic, solid, and metastatic tumor models and is accompanied by increased T cell persistence. Further, ZC3H12C is enriched in clinical pre-infusion CAR T cell products associated with non-response. Together, these findings identify ZC3H12C as a T cell dysfunction-specific target to improve ACT performance.

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↗

bioRxiv2024

Non-invasive visualization of pH changes within the tumor-micro-environment by positron emission tomography

Slight changes in the pH value of the tumor microenvironment (TME) have crucial effects on host defense, metastatic behavior, immune regulation and cellular metabolism. Due to the high metabolic activity and insufficient perfusion of tumors, acidic metabolites often accumulate in tumors and can influence the pH of the TME. Several studies have shown that the acidity of the interstitial space and the relatively stable intracellular pH can influence the functions of cancer and stromal cells and their interaction with the extracellular matrix. We describe radiopharmaceutical probes for positron emission tomography (PET) that exploits the increasingly used concept of pH-dependent intratumorally cleavage of PET-tracer to release functional moieties. The radiopharmaceuticals are based on [18F]FDG, a PET tracer, routinely used, and substituents that are pH-dependently cleaved. Utilizing preclinical models, we were able to visualize small pH differences in the acidic TME of different tumors with [18F]FDG-4-methoxybenzylamine ([18F]FDG-4MBA). In vivo studies were in line with in vitro results and showed that the hemiaminal bond between FDG and a substitute is cleaved at slightly acidic pH and leads to pH dependent radiotracer uptake. In vivo neutralization of the acidic extracellular tumor pH by sodium bicarbonate treatment prevents pH-dependent cleavage of [18F]FDG-4MBA and a resulting decrease of uptake. The determination of pH differences in acidic TME may serve as a novel marker for various questions such as regulation of the response to immunotherapies. Notably, even small pH differences in the acidic TME of different tumors, in the same in vivo model, could be visualized. This is the first preclinical study to show that it is possible to visualize small pH differences in the TME of different tumors in the same mouse using hemiaminal bound [18F]FDG. Due to the facile tracer synthesis and application, this system could be well suited for translation into clinical studies to develop new strategies of pH regulation to improve the efficacy of immunotherapy in cancer patients. graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/624628v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1c338c8org.highwire.dtl.DTLVardef@1c4fc67org.highwire.dtl.DTLVardef@197036aorg.highwire.dtl.DTLVardef@1613fa2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

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↗