Biology subjects

Hamdan, F. H.

Publications and source records attributed to Hamdan, F. H..

3 recordsLinked to original sources

bioRxiv2026

Cytotoxic CD4+ exTregs expressing KLRG1 retain immunosuppressive function in cancer

The role of cytotoxic CD4+ T cells in cancer remains controversial, with both pro- and anti-tumor functionality described. Based on a prior observation that putatively cytotoxic KLRG1+ FoxP3- conventional T cells (Tconv) associated with tumor progression, we deeply investigated the phenotype and function of KLRG1+ Tconv in multiple murine tumor models and in human clear cell renal cell carcinoma (ccRCC) specimens. We found KLRG1+ Tconv have a conserved, highly activated, terminally differentiated phenotype across species. In murine tumors, KLRG1+ Tconv resemble tumor-infiltrating regulatory T cells (Tregs) at both transcriptional and proteomic levels, upregulating a spectrum of exhaustion-related checkpoint receptors, producing IL-10 and granzyme B (GzmB), and silencing expression of IFN{gamma} and TNF. Functionally, KLRG1+ Tconv exhibited immunosuppressive function in ex vivo assays. Using an in vivo Treg fate mapping approach in tumor-bearing mice, we found a subset of KLRG1+ Tconv are derived from Tregs that have lost FoxP3 protein expression. Ex vivo functional assays demonstrated the exTreg component of the KLRG1+ Tconv compartment is responsible for IL-10 production and reduced pro-inflammatory cytokine expression. In treatment studies, we found that KLRG1-targeted antibody-mediated depletion was more efficient than anti-KLRG1 blockade at slowing tumor growth and improving survival, with responses associating with depletion of intratumoral KLRG1+ Tconv and Tregs. In sum, our study discovered a novel conserved pathway of CD4+ T cell plasticity, wherein intratumoral, cytotoxic KLRG1+ CD4+ Tconv cells can be derived from Tregs and maintain immunosuppressive function, despite loss of FoxP3, and that KLRG1-targeted depletion may outperform KLRG1 blockade as an immunotherapeutic strategy in cancer.

immunology↗

bioRxiv2026

Extended normothermic machine perfusion preserves viability and tissue integrity of ex vivo human intestine segments

Human intestinal diseases, including inflammatory bowel disease (IBD), are difficult to model because existing animal and in vitro systems do not capture the integrated vascular, immune, and metabolic complexity of the intestine. Here, we establish a custom normothermic machine perfusion platform that maintains surgically resected human intestinal tissue for up to 72 hours under near-physiological conditions. Discarded specimens from patients with nonmalignant intestinal diseases, including IBD and diverticulitis, were continuously perfused at 37{degrees}C with real-time hemodynamic and metabolic monitoring. Perfusion preserved tissue viability, mucosal architecture, epithelial integrity, oxygen consumption, metabolic activity, and vascular patency. Daily perfusate sampling enabled longitudinal profiling and experimental modulation of inflammatory mediators, revealing patient-specific immune states. This long-duration platform bridges reductionist in vitro models and clinical disease, enabling mechanistic studies of intestinal inflammation and future testing of personalized therapies in intact patient-derived tissue.

bioengineering↗

bioRxiv2025

Intestinal Stem Cells Retain an Epigenetic Memory of Prior Inflammation

Intestinal epithelial damage and impaired repair are hallmarks of ulcerative colitis (UC), even after inflammation resolves. Intestinal stem cells (ISCs) can retain stable epigenetic changes after inflammation, highlighting the potential for long-lived epithelial memory in the gut. Inflammatory injury in barrier tissues induces epigenetic memory in epithelial stem cells, and the tendency of UC to relapse at previously inflamed sites led us to hypothesize that ISCs from IBD patients acquire lasting memory of prior inflammation. To test this, we derived colonic organoids from inflamed and uninflamed regions of the same UC patients and propagated in long-term culture. Chromatin profiling revealed 2,252 accessible regions unique to prior-inflamed (PI) organoids, associated with stress response, repair, and inflammatory genes. Although these regions remained accessible, [~]95% of associated genes were not upregulated in PI organoids, indicating a primed state. Upon inflammatory or injury re-challenge, PI organoids exhibited heightened transcriptional responses and accelerated wound closure, despite reduced clonogenicity and impaired barrier function, indicating a retained inflammatory memory program. Our findings demonstrate that human ISCs retain a chromatin-based memory of inflammation that persists in the absence of immune cues and shapes future responses to injury. While this may support epithelial adaptation to secondary insults, it may predispose tissue to relapse in patients with UC.

molecular biology↗