Biology subjects

Socie, G.

Publications and source records attributed to Socie, G..

3 recordsLinked to original sources

bioRxiv2025

Corticosteroid resistance is predetermined by early immune response dynamics at acute Graft Versus Host disease onset

Steroid-resistant acute graft versus host disease (SR-aGVHD) is the leading life-threatening complication following allogeneic hematopoietic stem cell transplantation. Novel therapeutics development is impeded by scares knowledge on biological pathways leading to steroid resistance at time of aGVHD diagnosis. To gain insight into our understanding on circulating immune cell subsets and functions at time of aGVHD, a single cell deep phenotyping and transcriptome analysis was performed on peripheral blood mononuclear cells from patients with aGVHD before steroid treatment or without aGVHD. We aimed at identifying biological patterns associated with steroid resistance at early onset of aGVHD. First, circulating immune cell subsets were associated with increased incidence of aGVHD, but not with steroid sensitivity. Then, pathway analysis and inferred ligand/receptor interactions revealed major functional divergences between steroid-sensitive (SS-) and SR-aGVHD, including enrichment of TNF activation in SR-GVHD, as well as TNF/TNFR, CCL3, CCL4 and IL18 signaling, and decreased interferon and {gamma} signaling pathways, suggesting that steroid resistance in an intrinsic property of immune cells before any treatment. To go deeper into the understanding of mechanisms at play during SR-aGVHD, we modeled immune trajectories within CD8+ T cells and evidenced specific direct transition, from an early naive state to a highly activated one. By contrast, SS-aGVHD involved specific gene signatures across multiple intermediate differentiation stages during cell-to-cell transitions. These findings provide evidence that steroid resistance is driven by intrinsic mechanisms already present at the onset of alloimmune response, that may serve as potential new therapeutic targets.

molecular biology↗

bioRxiv2024

A spatial atlas of human gastro-intestinal acute GVHD reveals epithelial and immune dynamics underlying disease pathophysiology

Acute graft-versus-host disease (aGVHD) is a significant complication of allogeneic hematopoietic stem cell transplantation (aHSCT), driven by alloreactive donor T cells in the gut. However, the roles of additional donor and host cells in this process are not fully understood. We conducted multiplexed imaging on 59 biopsies from patients with gastrointestinal GVHD and 10 healthy controls, revealing key pathological changes, including fibrosis, crypt alterations, loss of Paneth cells, accumulation of endocrine cells, and disrupted immune organization, particularly a reduction in IgA-secreting plasma cells. Interestingly, CD8T cells were enriched only in a subset of patients, while others exhibited non-canonical enrichments of macrophages and neutrophils. Post-transplantation time significantly influenced immune composition, with host cells dominating plasma and T cell compartments long after transplantation. This spatial atlas of healthy duodenum and GVHD uncovers non-canonical immune dynamics, offering insights into disease pathophysiology and potential clinical applications in GVHD and other inflammatory bowel diseases.

immunology↗

bioRxiv2021

In vivo genome-wide CRISPR screens identify SOCS1 as a major intrinsic checkpoint of CD4+ Th1 cell response

The expansion of antigen experienced CD4+ T cells is limited by intrinsic factors. Using in vivo genome-wide CRISPR-Cas9 screens, we identified SOCS1 as a non-redundant checkpoint imposing a brake on CD4+ T-cell proliferation upon rechallenge. We show here that SOCS1 is a critical node integrating both IL-2 and IFN-{gamma} signals and blocking multiple signaling pathways to abrogate CD4+ Th1 cell response. In CD8+ T-cell, SOCS1 does not impact the proliferation but rather reduces survival and effector functions. By targeting SOCS1, both murine and human CD4+ T-cell antitumor adoptive therapies exhibit a restored intra-tumor accumulation, proliferation/survival, persistence and polyfunctionality, promoting long term rejection of established tumors. These findings identify SOCS1 as a major intracellular checkpoint inhibitor of primed CD4+ T cells, opening new possibilities to optimize CAR-T cell therapies composition and efficacy.

immunology↗