Biology subjects

Kenigsberg, E.

Publications and source records attributed to Kenigsberg, E..

7 recordsLinked to original sources

bioRxiv2026

A JAK-STAT-activated myeloid hub at ulceration sites underlies resistance to anti-TNF therapy in Crohn's disease

Despite major advances in immunotherapies, durable disease control in immune-mediated inflammatory diseases (IMIDs) is frequently limited by resistance driven by maladaptive immune programs, resulting in progressive tissue damage. Myeloid cells are central effectors across IMIDs, including inflammatory bowel disease (IBD), yet how discrete myeloid states govern disease progression and therapeutic response remains incompletely defined. Here, using integrative single-cell transcriptomic and molecular analyses of inflamed human ileum in Crohns disease (CD), we identify combinatorial transcriptional programs that revealed previously unrecognized axes of monocyte-macrophage (mo-mac) heterogeneity. These myeloid states and programs were conserved and validated across multiple independent cohorts. We delineate a pathogenic mo-mac subset, interferon-associated inflammatory monocytes (IFIM), shaped by convergent NF-{kappa}B and IFN{gamma} signaling and enriched in advanced disease. Baseline abundance of IFIM programs predicted resistance to anti-TNF therapy and severe postoperative recurrence, with IFIM-derived ligands sustaining epithelial injury. IFIM exhibited robust JAK-STAT activation, indicating susceptibility to JAK inhibition with clinically approved agents, including upadacitinib. Exemplified by IFIM-driven inflammation, these findings identify pathogenic myeloid state remodeling as a molecular basis of anti-TNF resistance and provide a framework for mechanism-guided therapeutic strategies across chronic inflammatory diseases.

immunology↗

bioRxiv2022

Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade

Here, we leveraged a large neoadjuvant PD-1 blockade trial in patients with hepatocellular carcinoma (HCC) to search for correlates of response to immune checkpoint blockade (ICB) within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13+ CH25H+ IL-21+ PD-1+ CD4 T helper cells (CXCL13+ Th) and Granzyme K+ PD-1+ effector-like CD8 T cells, whereas terminally exhausted CD39hi TOXhi PD-1hi CD8 T cells dominated in non-responders. Strikingly, most T cell receptor (TCR) clones that expanded post-treatment were found in pre-treatment biopsies. Notably, PD-1+ TCF-1+ progenitor-like CD8 T cells were present in tumors of responders and non-responders and shared clones mainly with effector-like cells in responders or terminally differentiated cells in non-responders, suggesting that local CD8 T cell differentiation occurs upon ICB. We found that these progenitor CD8 T cells interact with CXCL13+ Th cells within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or "mregDC". Receptor-ligand analysis revealed unique interactions within these triads that may promote the differentiation of progenitor CD8 T cells into effector-like cells upon ICB. These results suggest that discrete intratumoral niches that include mregDC and CXCL13+ Th cells control the differentiation of tumor-specific progenitor CD8 T cell clones in patients treated with ICB.

immunology↗

bioRxiv2022

Spatial positioning and matrix programs of cancer-associated fibroblasts promote T cell exclusion in human lung tumors

It is currently accepted that activated cancer-associated fibroblasts (CAF) participate in T cell exclusion from tumor nests, but it remains unclear how they promote barrier phenotypes, and whether specific subsets are involved. Here, using single-cell RNA sequencing coupled with multiplex imaging on a large cohort of lung tumors, we identify four main CAF populations, of which only two are associated with T cell exclusion: (i) MYH11+SMA+ CAF, which are present in early-stage tumors and form a single-cell layer lining cancer aggregates, and (ii) FAP+SMA+ CAF, which appear in more advanced tumors and organize in patches within the stroma or in multiple layers around tumor nests. Both CAF populations show a contractility phenotype together with dense and aligned matrix fiber deposition compared to the T cell-permissive CAF. Yet they express distinct matrix genes, including COL4A1/COL9A1 (MYH11+SMA+ CAF) and COL11A1/COL12A1 (FAP+SMA+ CAF). Hereby, we uncovered unique molecular programs of CAF driving T cell marginalization, whose targeting should increase immunotherapy efficacy in patients bearing T cell-excluded tumors. SIGNIFICANCEThe cellular and molecular programs driving T cell marginalization in solid tumors remain unclear. Here, we describe two CAF populations associated with T cell exclusion in human lung tumors. We demonstrate the importance of pairing molecular and spatial analysis of the tumor microenvironment, a prerequisite to develop new strategies targeting T cell-excluding CAF.

cancer biology↗

bioRxiv2022

Shift of lung macrophage composition is associated with COVID-19 disease severity and recovery

Though it has been 2 years since the start of the Coronavirus Disease 19 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, very little progress has been made to identify curative therapies to treat COVID-19 and other inflammatory diseases which remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and death to develop tailored immunotherapy strategies to halt disease progression. Here we assembled the Mount Sinai COVID-19 Biobank which was comprised of ~600 hospitalized patients followed longitudinally during the peak of the pandemic. Moderate disease and survival were associated with a stronger antigen (Ag) presentation and effector T cell signature, while severe disease and death were associated with an altered Ag presentation signature, increased numbers of circulating inflammatory, immature myeloid cells, and extrafollicular activated B cells associated with autoantibody formation. Strikingly, we found that in severe COVID-19 patients, lung tissue resident alveolar macrophages (AM) were not only severely depleted, but also had an altered Ag presentation signature, and were replaced by inflammatory monocytes and monocyte-derived macrophages (MoM{Phi}). Notably, the size of the AM pool correlated with recovery or death, while AM loss and functionality were restored in patients that recovered. These data therefore suggest that local and systemic myeloid cell dysregulation is a driver of COVID-19 severity and that modulation of AM numbers and functionality in the lung may be a viable therapeutic strategy for the treatment of critical lung inflammatory illnesses.

immunology↗

bioRxiv2020

CITEseq analysis of non-small-cell lung cancer lesions reveals an axis of immune cell activation associated with tumor antigen load and TP53 mutations

Immunotherapy is becoming a mainstay in the treatment of NSCLC. While tumor mutational burden (TMB) has been shown to correlate with response to immunotherapy, little is known about the relation of the baseline immune response with the tumor genotype. Here, we profiled 35 early stage NSCLC lesions using multiscale single cell sequencing. Unsupervised clustering identified in a subset of patients a key cellular module consisting of PDCD1+ CXCL13+ activated T cells, IgG+ plasma cells, and SPP1+ macrophages, referred to as the lung cancer activation module (LCAMhi). Transcriptional data from two NSCLC cohorts confirmed a subset of patients with LCAMhi enrichment, which was independent of overall immune cell content. The LCAMhi module strongly correlated with TMB, expression of cancer testis antigens, and with TP53 mutations in smokers and non-smokers. These data establish LCAM as a key mode of immune cell activation associated with high tumor antigen load and driver mutations.

immunology↗

bioRxiv2019

Serum Amyloid A Proteins Induce Pathogenic TH17 Cells and Promote Inflammatory Disease

Lymphoid cells that produce IL-17 cytokines protect barrier tissues from pathogenic microbes, but are also prominent effectors of inflammation and autoimmune disease. T-helper (TH17) cells, defined by ROR{gamma}t-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naive CD4+ T cells. In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, TH17 cell behaviors vary markedly according to their environment. Here we show that SAAs additionally direct a pathogenic pro-inflammatory TH17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss- and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting TH17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies.

immunology↗

bioRxiv2018

Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy

Clinical benefits to cytokine blockade in ileal Crohns disease (iCD) have been limited to a subset of patients. Whether cellular and molecular heterogeneity contributes to variability in treatment responses has been unclear. Using single cell technologies combining scRNAseq, CyTOF and multiplex tissue imaging, we mapped the cellular landscape of inflamed ileum lesions, adjacent non-inflamed ileum and matched circulating blood cells of iCD patients. In inflamed tissues, we identified a pathogenic module characterized by an inflammatory mononuclear phagocyte (Inf.MNP)-associated cellular response organized around inflammatory macrophages and mature dendritic cells in a subset of iCD patients. We confirmed the Inf.MNP-associated cellular response in 4 independent iCD cohorts (n=441) and showed that presence of this pathogenic module at diagnosis correlated with primary resistance to anti-TNF therapy. Single cell mapping of iCD tissues identifies a complex cellular signature of anti-TNF resistance thereby revealing novel biomarkers of treatment response and tailored therapeutic opportunities.

immunology↗