Biology subjects

Bendriss-Vermare, N.

Publications and source records attributed to Bendriss-Vermare, N..

8 recordsLinked to original sources

bioRxiv2025

Refined cellular activity expression signatures provide a targeted framework to quantify phenotypic intra-tumor heterogeneity in single-cell data

Single cell RNA-seq (scRNA-seq) now allows deeper insight into cellular biology at both the individual and population level. Measuring cell-to-cell variations in the population enables quantification of phenotypic heterogeneity in populations in which cell states and identities deviate from healthy transcriptomic profiles. Cellular activities quantifiable using gene set enrichment analyses can provide useful grounds to quantify phenotypic heterogeneity, but the specificity and adequacy of existing molecular signatures for scRNA-seq data is still insufficient. Here we induced 6 activities in vitro, for which we refined existing expression signatures to enhance specificity and detection in scRNA-seq data: epithelial-mesenchymal transition (EMT), DNA repair, responses to interferons and {gamma} (IFN and IFN{gamma}, respectively), glycolysis, oxidative phosphorylation (OxPhos). We report new signatures, with much lower redundancy between IFN and IFN{gamma}, and glycolysis and OxPhos signatures, achieving average AUCs of 0.85 across bootstrapped datasets for each activity. We could use these signatures to quantify phenotypic intra-tumor heterogeneity (ITH) in 20 patient samples and 14 cell lines, observing high correlation with diversity indices in classified healthy cells (p<0.001). Focusing on cancer cells only, we furthermore report higher phenotypic ITH in patients than in cell lines (p<0.001), and in basal tumors (p=0.028).

cancer biology↗

bioRxiv2025

IntegrAlign: A comprehensive tool for multiimmunofluorescence panel integration through image alignment

MotivationTyramide-based multiplex-immunofluorescence (mIF) enables the simultaneous analysis of up to seven protein markers on a whole slide, providing a comprehensive approach to study the tumor microenvironment. Integrating multiple mIF panels through image alignment of serial slide significantly expands the number of cell populations analyzed in a single space. IntegrAlign was developed to optimize this integration on serial whole slides, enhancing the value and applicability of mIF for comprehensive spatial analyses and enabling biomarker discovery at scale. ResultsIntegrAlign, leveraging the SimpleITK toolkit, applies a two-step alignment using rigid and B-spline transformations to integrate serial mIF whole slides. Validation on simulated and real datasets demonstrated alignment accuracy below the diameter of a cell nucleus ([~]6 {micro}m), outperforming existing methods. This precision enhances spatial analyses by combining extended phenotypic data, supporting novel insights into tissue architecture and cellular interactions. Availability and ImplementationIntegrAlign is open-source, implemented in Python, and freely available under the MIT license at https://github.com/CAUXlab/IntegrAlign.

bioinformatics↗

bioRxiv2025

Oncogenic Stress is a Novel Immunogenic Signal Driven by the Unfolded Protein Response and Detected by Neutrophils

Breast cancer (BC) is the leading cause of cancer-related death in women. However, early detection of BC remains a major clinical challenge and represents a significant obstacle to effective prevention. To improve early clinical management, a deeper understanding of the preneoplastic immune microenvironment of BC is crucial. Among innate immune populations, neutrophils have emerged as important modulators of tumor development, but their role during the initiation of BC remains poorly understood. By integrating depletion experiments with transcriptomic profiling of sorted preneoplatic epithelial cells and neutrophils in spontaneous breast cancer mouse models, we observed that neutrophils contribute to tumor surveillance of preneoplastic stage with the activation of the unfolded protein response (UPR) in the preneoplastic epithelial compartment. To decipher the early anti-tumoral role of neutrophil, we developed an in vitro co-culture model of human mammary epithelial cells undergoing oncogenic stress with activation of the UPR (eHMEC), with human primary neutrophils. eHMEC display an immunoactive secretome as well as immunogenic membrane ligands, and neutrophils are the only immune cell population detecting eHMEC immunogenic signals leading to their recruitment, activation, production of reactive oxygen species and degranulation. Altogether, our work identifies for the first-time neutrophils as the earliest immune cell involved in immunosurveillance of preneoplastic BC epithelial cells, paving the way for potential therapeutic approaches targeting neutrophils to intercept early steps of BC tumorigenesis.

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↗

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↗

bioRxiv2023

CD4 T cells and neutrophils contribute to epithelial-mesenchymal transition in breast cancer

Epithelial-mesenchymal transition (EMT) is a central oncogenic mechanism, contributing both to transformation and metastatic dissemination. Inflammation and innate immune cells are known to favor EMT induction, but the role of adaptive immunity still remains unclear. Using an original murine mammary tumor model in immune cell subpopulation depletion experiments, we demonstrated that tumor cells maintain their epithelial phenotype in mice deficient for adaptive immune response, but undergo EMT in the presence of T-cells. This phenotypic conversion involves the major contribution of CD4 T cells, but not CD8 T cells nor B cells, undoubtedly demonstrating the pro-EMT role of CD4 T cells specifically among adaptive immune cells. Moreover, combined intra-tumor immune infiltrate and transcriptomic analyses of murine mammary tumors with various EMT phenotype revealed an inverse correlation between mesenchymal tumor cell and intratumoral neutrophil proportions, due to the reduced ability of mesenchymal cells to recruit neutrophils. Last, selective in vivo depletion of neutrophils and transcriptomic analysis of human breast tumor cohorts demonstrated the pro-EMT role of neutrophils and suggest a cooperation with CD4 T cells in EMT promotion. Collectively, our data highlight a novel mechanism of EMT regulation by both innate and adaptive immune compartments.

cancer biology↗

bioRxiv2020

cDC1 and interferons promote spontaneous CD4+ and CD8+ T cell protective responses to breast cancer

Here we show that efficient breast cancer immunosurveillance relies on cDC1, conventional CD4+ T cells, CD8+ cytotoxic T lymphocytes (CTL) and later NK/NK T cells. For this process, cDC1 were required constitutively, but especially during the T cell priming phase. In the tumor microenvironment, cDC1 interacted physically and jointly with both CD4+ T cells and tumorspecific CD8+ T cells. We found that interferon (IFN) responses were necessary for the rejection of breast cancer, including cDC1-intrinsic signaling by IFN-{gamma} and STAT1. Surprisingly, cell-intrinsic IFN-I signaling in cDC1 was not required. cDC1 and IFNs shaped the tumor immune landscape, notably by promoting CD4+ and CD8+ T cell infiltration, terminal differentiation and effector functions. XCR1, CXCL9, IL-12 and IL-15 were individually dispensable for breast cancer immunosurveillance. Consistent with our experimental results in mice, high expression in the tumor microenvironment of genes specific to cDC1, CTL, helper T cells or interferon responses are associated with a better prognosis in human breast cancer patients. Our results show that immune control of breast cancer depends on cDC1 and IFNs as previously reported for immunogenic melanoma or fibrosarcoma tumor models, but that the underlying mechanism differ. Revisiting cDC1 functions in the context of spontaneous immunity to cancer should help defining new ways to mobilize cDC1 functions to improve already existing immunotherapies for the benefits of patients. SynopsisType 1 conventional dendritic cells cross-present tumor antigens to CD8+ T cells. Understanding the regulation of their antitumor functions is important. Cell-intrinsic STAT1/IFN-{gamma} signaling licenses them for efficient CD4+ and CD8+ T cell activation during breast cancer immunosurveillance.

immunology↗

bioRxiv2018

Efficient and specific Ly6G+ cell depletion: A change in the current practices toward more relevant functional analyses of neutrophils

Neutrophils orchestrate the innate immune response against microorganisms and are increasingly recognized to modulate cancer development in primary tumors and metastases. To address their function in vivo, different approaches are used, the most common ones relying on antibody-mediated neutrophil depletion. By comparing the effects of two widely used antibodies, we demonstrate a strong efficacy but a lack of specificity for anti-Gr1. In contrast, anti-Ly6G lacks neutrophil-depletion capacity in C57BL/6 mice, which can be explained by an insufficient celerity of neutrophil clearance that is counterbalanced by exacerbated mobilization of immature cells. When combined with a secondary antibody, anti-Ly6G treatment results in specific and efficient neutrophil depletion. Using a mouse model of lung adenocarcinoma, we demonstrate the efficacy of this new approach to diminish primary tumor growth and propose the existence of a local intercellular communication between neutrophils and alveolar macrophages that fosters regulatory T cell proliferation in lung cancer.

immunology↗