Biology subjects

Walzer, T.

Publications and source records attributed to Walzer, T..

9 recordsLinked to original sources

bioRxiv2026

Glycometabolic, inflammatory and exocrine plasma proteins predict cancer in individuals with cardiovascular disease

Cancer development is preceded by systemic immune, metabolic and tissue perturbation. We asked whether a minimal circulating-protein signature anticipates incident cancer in patients with atheromatous cardiovascular disease (ACVD) exposed to tobacco. Discovery used a nested case-control set drawn from the longitudinal FLEMENGHO cohort (n=156; 38 incident lung cancers). Multi-omic profiling returned a two-step classifier: four proteins, smoking status, personal cancer history. Preprocessing constants, classifiers and both thresholds were fixed before transfer to PREVALUNG (n=397; 58 incident cancers, 26 of them lung). There, low O-GlcNAcase (OGA) with low interleukin-6 (IL-6) defined a very-low-risk stratum holding 1 of 58 cancers (sensitivity 98.3%, negative predictive value 98.8%); low chymotrypsin C (CTRC) with high beta microseminoprotein (MSMB) defined a high-risk stratum in which 15 of 28 participants developed cancer. No additional omic feature (metabolomic, immunophenotypic, clonal-haematopoietic or metagenomic) was retained as a reproducible improvement to the classifier under our selection framework. Discrimination was greater for cancers diagnosed more than 12 months after sampling than for near-term cancers (AUC 0.766, 95% CI 0.671-0.857, versus 0.589, 0.485-0.692), arguing against performance being driven principally by occult disease. These estimates are conditional on the cancer frequency of this population. They require prospective confirmation before any imaging schedule is changed.

cancer biology↗

bioRxiv2025

Immunological and clinical markers of post-acute sequelae of COVID-19: Insights from mild and severe cases six months post-infection

Post-acute sequelae of COVID-19 (PASC) is a complex and multifaceted clinical challenge requiring to emphasize its underlying pathophysiological mechanisms. This study assessed hundreds of virological, serological, immunological, and tissue damage biomarkers in two patient cohorts who experienced mild (n=270) or severe (n=188) COVID-19, 6 to 9 months post-initial infection, and in which 40% and 57.4% of patients, respectively, developed PASC. Blood analysis showed that mains differences observed in humoral, viral, and biological biomarkers were associated with the initial COVID-19 severity, rather than being specifically linked to PASC. However, patients with PASC displayed altered CD4+ and CD8+ memory T-cell subsets, with higher cytokine-secreting cells and increased terminally differentiated CD45RA+ effector memory T cells (TEMRA). Elevated SARS-CoV-2-specific T cells responsive to nucleocapsid/membrane proteins with a TEMRA phenotype were also observed. A random forest model identified these features and initial symptom duration as top variables discriminating PASC, achieving over 80% classification accuracy. HighlightsO_LINine months post-initial SARS-CoV-2 infection, over 40% of patients developed PASC C_LIO_LIRegardless of PASC, the initial disease form influenced the main immune differences C_LIO_LIPASC led to altered memory T-cell subsets with elevated TEMRA phenotype C_LIO_LIPASC presence is associated with disease form, initial symptom count and duration C_LI

immunology↗

bioRxiv2024

Memory-Phenotype Ly49+ CD8 T emerging from the thymus develop into two subsets with distinct immune functions

Ly49+ CD8 T cells are memory-phenotype (MP) cells expressing Ly49 family inhibitory receptors, that control autoimmune diseases development through the regulation of follicular CD4 T cells. During viral infection, their number increases, suggesting an involvement in antiviral responses. These cells do not derive from naive cells and are thought to develop in the thymus. This study identified two subsets of Ly49+ CD8 T cells, based on CD8{beta} expression, in mice and humans. Lineage tracing and reliance on the transcription factor Zeb1 indicate a thymic origin via agonist selection. scRNAseq analysis revealed that a small fraction of CD8{beta}-Ly49+ cells acquired an effector profile during vaccinia virus infection. Moreover, the majority of Ly49+ CD8 T cells seems to respond to cytokine-driven bystander signals. In vitro, these signals promoted the expression of effector molecules such as IFN{gamma} and granzyme B, as well as the homing chemokine receptor CXCR5, potentially driving their recruitment to germinal centers. SummaryThis study shows that Ly49+ CD8 T cells comprises two subsets that develop in the thymus through agonist selection. In viral infection, both subsets respond to bystander stimuli that could drive their regulatory activity. Furthermore, some CD8{beta}-expressing Ly49+ cells exert TCR-mediated antiviral response.

immunology↗

bioRxiv2024

Adaptive immunity shapes innate and epithelial cell landscapes by silencing tonic IFN-gamma in innate lymphoid cells during homeostasis.

During homeostasis, innate and epithelial cells undergo continuous maturation, shaped by microbial, molecular and cellular interactions. While these cells influence adaptive immunity during steady-state conditions, the reciprocal homeostatic role of adaptive immune cells in the maturation and function of innate and epithelial cells remains underexplored. Here, through computational approaches and murine models, we establish that adaptive immunity shapes innate immune and epithelial homeostatic landscapes. Mechanistically, adaptive immunity acts as a brake on type 1 polarization and diversification of innate lymphocytes (ILCs). Without adaptive immunity, the innate cellular interactions within the mesenteric lymph nodes are dominated by an interferon-gamma (IFN{gamma}) signaling network. Moreover, the innate immune and epithelial cells follow distinct phenotypic and functional trajectories, including ILCs acquiring myeloid markers, monocytes adopting an inflammatory path, and colonic epithelial cells expressing altered antimicrobial peptides and losing Paneth-like features. Depleting ILCs, abolishing IFN{gamma} signaling, or restoring adaptive immunity reduces these IFN{gamma}-driven changes. Thus, our findings highlight a homeostatic function of adaptive immunity in modulating innate and epithelial cell communication, diversity, composition, function, and differentiation, notably by limiting ILC-derived IFN{gamma}.

immunology↗

bioRxiv2024

Loss of TLR9 expression in breast cancer tumour cells and its role in the cell cycle.

Toll-like receptor 9 (TLR9), primarily expressed in human dendritic and B cells, recognizes double-stranded DNA motifs from pathogens, initiating an inflammatory response. Recent studies have revealed TLR9s involvement beyond its conventional role in immune response, notably during the tumorigenesis of various cancers such as head and neck, cervical, and ovarian cancers. Here we show by immunohistochemistry analysis demonstrated significantly lower TLR9 levels in breast cancer tumors compared to normal breast tissue epithelium. Similarly, TLR9 downregulation was also observed in several transformed breast cancer cell lines versus untransformed breast epithelial cell lines. Furthermore, overexpression of TLR9 led to reduced proliferation potential of breast cancer cell associated with activation of senescence as was evident by upregulation of proinflammatory cytokine IL-6, chemokines IL-8 and CXCL1; and growth factor GM-CSF. These findings support TLR9s regulatory role in mitigating breast cancer and highlight its critical connection between the inflammatory response and tumor immunity.

cell biology↗

bioRxiv2024

Inflamed Natural Killer cells with adhesion defects are associated with a poor prognosis in Multiple Myeloma

The promising results obtained with immunotherapeutic approaches for multiple myeloma (MM) call for a better stratification of patients based on immune components. The most pressing being cytotoxic lymphocytes such as Natural Killer (NK) cells that are mandatory for MM surveillance and therapy. In this study, we performed a single cell RNA sequencing analysis of NK cells from 10 MM patients and 10 age/sex matched healthy donors (HD) that revealed important transcriptomic changes in NK cell landscape affecting both the bone marrow and peripheral blood compartment. The frequency of mature cytotoxic "CD56dim" NK cell subsets was reduced in MM patients at the advantage of late-stage NK cell subsets expressing NF{kappa}B and IFN-I inflammatory signatures. These NK cell subsets accumulating in MM patients were characterized by a low CD16 and CD226 expression and poor cytotoxic functions. MM CD16/CD226lo NK cells also had adhesion defects with reduced LFA-1 integrin activation and actin polymerization that may account for their limited effector functions in vitro. Finally, analysis of BM infiltrating NK cells in a retrospective cohort of 177 MM patients from the IFM 2009 trial demonstrated that a high frequency of NK cells and their low CD16 and CD226 expression were associated with a shorter overall survival. Thus, CD16/CD226lo NK cells with reduced effector functions accumulate along MM development and negatively impact patients clinical outcome. Given the growing interest in harnessing NK cells to treat myeloma, this improved knowledge around MM-associated NK cell dysfunction will stimulate the development of more efficient immunotherapeutic drugs against MM. Scientific category: Lymphoid Neoplasia; Immunobiology and Immunotherapy. KEY POINTSO_LIMM patients have increased CD16/CD226low NK cell subsets characterized by "inflammatory" signatures and reduced effector functions. C_LIO_LIThe frequency of CD16/CD226low NK cells correlate with MM patient clinical outcome C_LI

immunology↗

bioRxiv2023

IL-33 drives polyfunctionality and antitumor activity of a unique ST2+ NK cell population

Despite increasing recognition of NK cell diversity, their functional heterogeneity and its relevance to cancer remain incompletely understood. Here, we show that IL-12 promotes the emergence of a distinct ST2/IL33R+ NK cell state poised for robust activation by IL-33. Human ST2 NK cells exhibit a unique transcriptional program, an intermediate differentiation state between CD56bright and CD56dim NK cells, and enhanced polyfunctionality combining proliferation, cytokine production, and cytotoxicity. ST2 NK cells were identified across human and murine tumor datasets. In murine breast cancer models, IL-33 and IL-12 cooperated to elicit potent antitumor responses dependent on IFN-{gamma} and ST2 NK cells. In cancer patients, IL-12 unleashed tumor-infiltrating ST2 NK cells' potential to produce IFN-g in response to IL-33, an IL33hi-NKhi score was associated with prolonged survival, and ST2 NK cells correlated with improved immunotherapy response. Collectively, these findings identify ST2 NK cells as a therapeutically actionable NK cell state promoting antitumor immunity.

cancer biology↗

bioRxiv2020

Peripheral Natural Killer cells from chronic hepatitis B patients display molecular hallmarks of T cell exhaustion

A significant proportion of individuals infected by HBV develops chronic infection. Antiviral effectors such as Natural Killer (NK) cells have impaired functions in these patients, but the molecular mechanism responsible for this dysfunction remains poorly characterized. Here, we show that peripheral NK cells from chronic hepatitis B (CHB) patients have a defective capacity to produce IFN-{gamma}, MIP1-{beta} and TNF- but retain an intact killing capacity. This functional phenotype was associated with a decrease in the expression of NKp30 and CD16, combined with defects in IL-15 stimulation of the mTOR pathway. Transcriptome analysis of NK cells in CHB patients further revealed a strong enrichment for transcripts typically expressed in exhausted T cells suggesting that NK cell dysfunction and T cell exhaustion rely on common molecular mechanisms. In particular, the transcription factor thymocyte selection-associated HMG box protein (TOX) and several of its targets, including immune checkpoints, were over-expressed in NK cells of CHB patients. This T cell exhaustion signature was predicted to be dependent on the calcium (Ca2+)-associated transcription factor NFAT. In line with this, when stimulating the Ca2+-dependent pathway in isolation, we recapitulated the dysfunctional phenotype. Thus, deregulated Ca2+ signalling could be a central event in both T cell exhaustion and NK cell dysfunction that occur during chronic infections.

immunology↗

bioRxiv2017

Antigen-induced but not innate memory CD8 T cells express NKG2D and are recruited to the lung parenchyma upon viral infection

The pool of memory-phenotype CD8 T cells is composed of antigen-induced (AI) and cytokine-induced innate (IN) cells. IN have been described as having similar properties to AI memory cells. However, we found that pathogen-induced AI memory cells can be distinguished from naturally-generated IN memory cells by surface expression of NKG2D. Using this marker, we described the increased functionalities of AI and IN memory CD8 T cells compared to naive cells, as shown by comprehensive analysis of cytokine secretion and gene expression. However, AI differed from IN memory CD8 T cells by their capacity to migrate to the lung parenchyma upon inflammation or infection, a process dependent on their expression of ITGA1/CD49a and ITGA4/CD49d integrins.

immunology↗