Biology subjects

Ottensmeier, C. H.

Publications and source records attributed to Ottensmeier, C. H..

6 recordsLinked to original sources

bioRxiv2026

Dual-antigen Doggybone DNA vaccine induces potent anti-tumor immunity against immunosuppressive oral cancer

Anti-PD1 blockade benefits only a subset of patients with head and neck squamous cell carcinoma (HNSCC), highlighting the need for approaches that overcome tumor immune resistance. Here, using the doggybone DNA (dbDNATM) platform, we developed CaVac OPT, an optimized dual-antigen DNA vaccine targeting MAGED4B and FJX1, which are overexpressed in most HPV-negative HNSCC and multiple solid tumors. In the MOC-2 oral cancer model, CaVac OPT significantly reduced tumor growth and when combined with anti-PD1 therapy, further delayed progression and improved survival. Immune profiling showed increased infiltration of CD4+ and CD8+ T cells, expansion of stem-like Tcf1+ populations, without increase in regulatory T cells, a reduced M2/M1 macrophage ratio and activation of interferon gamma associated pathways with suppression of tumor-promoting signals. These findings demonstrate that CaVac OPT reprograms the tumor microenvironment, converting cold HNSCC into T cell-inflamed responsive tumors. CaVac OPT represents a promising strategy for achieving durable control of aggressive, immunotherapy-resistant head and neck cancer.

cancer biology↗

bioRxiv2024

Developmental programmes drive cellular plasticity, disease progression and therapy resistance in lung adenocarcinoma

BackgroundCellular plasticity, involving loss of lineage determination and emergence of hybrid cell states, plays a pivotal role in non-small cell lung cancer (NSCLC) disease progression and therapy resistance. However, the full spectrum of atypical states generated in human NSCLC and the pathways that regulate them are yet to be fully elucidated. Here we examine the role of developmental programmes, alveogenesis and branching morphogenesis (BM), in regulating phenotypic diversity in NSCLC. MethodsTranscriptomic analysis of epithelial cells isolated from murine lungs at different stages of organogenesis were used to derive gene signatures for developmental programmes. Bulk tissue transcriptomic datasets from human NSCLC and non-neoplastic control samples were used to identify whether developmental programmes were associated with molecular, morphological, and clinical parameters. Single-cell RNA-sequencing was used to identify malignant cell states in human NSCLC (n = 16,621 epithelial cells from 72 samples) and protein level validation of these states was carried out using multiplexed immunohistochemistry (n = 40). ResultsMutually antagonistic regulation of alveogenesis and BM was found to account for a significant proportion of transcriptomic variance in human NSCLC bulk tissue datasets. BM activation was associated with poor overall survival rates in five independent lung adenocarcinoma (LUAD) cohorts (p=2.04e-13); and was significantly prognostic for resistance to tyrosine kinase inhibitors (TKIs; p=0.003) and immune checkpoint blockade (ICBs; p=0.014), in pre-treatment biopsies. Single-cell RNA-sequencing analysis revealed that malignant LUAD cells with loss of alveolar lineage fidelity predominantly acquired inflamed or basal-like cellular states, which were variably persistent in samples from TKI and ICB recurrence. ConclusionsOur results show LUAD tumours undergo reversion from an alveogenic to branching morphogenic phenotype during disease progression, generating inflamed or basal-like cell states that are variably persistent following TKI or ICB treatments. These findings identify prognostic biomarkers for therapy response and underscore the role of different cell states in resistance to multiple treatment modalities.

cancer biology↗

bioRxiv2021

Transcriptomes and metabolism define mouse and human MAIT cell heterogeneity

Mucosal-associated invariant T (MAIT) cells are a subpopulation of T lymphocytes that respond to microbial metabolites. We performed single-cell RNA sequencing and metabolic analyses of MAIT cell subsets in thymus and peripheral tissues from mice and humans to define the heterogeneity and developmental pathway of these innate-like lymphocytes. We show that the predominant mouse subset, which produces IL-17 (MAIT17), and the subset that produces IFN{gamma} (MAIT1), have greatly different transcriptomes and metabolic states in the thymus and periphery. A splenic MAIT subset has a transcriptome similar to circulating lymphocytes, and in mice these also are found in recent thymic emigrants, suggesting partially mature cells emigrate from the thymus. Human MAIT cells are predominantly MAIT1 cells, but have a different metabolism from their mouse counterparts with increased fatty acid uptake and storage. Although mouse and human subsets are similar in thymus, in the periphery they diverge, likely reflecting environmental influences.

immunology↗

bioRxiv2020

COVID-19 genetic risk variants are associated with expression of multiple genes in diverse immune cell types.

Common genetic polymorphisms associated with severity of COVID-19 illness can be utilized for discovering molecular pathways and cell types driving disease pathogenesis. Here, we assessed the effects of 679 COVID-19-risk variants on gene expression in a wide-range of immune cell types. Severe COVID-19-risk variants were significantly associated with the expression of 11 protein-coding genes, and overlapped with either target gene promoter or cis-regulatory regions that interact with target promoters in the cell types where their effects are most prominent. For example, we identified that the association between variants in the 3p21.31 risk locus and the expression of CCR2 in classical monocytes is likely mediated through an active cis-regulatory region that interacted with CCR2 promoter specifically in monocytes. The expression of several other genes showed prominent genotype-dependent effects in non-classical monocytes, NK cells, B cells, or specific T cell subtypes, highlighting the potential of COVID-19 genetic risk variants to impact the function of diverse immune cell types and influence severe disease manifestations.

immunology↗

bioRxiv2020

Interplay of Monocytes and T Lymphocytes in COVID-19 Severity

The COVID-19 pandemic represents an ongoing global crisis that has already impacted over 13 million people. The responses of specific immune cell populations to the disease remain poorly defined, which hinders improvements in treatment and care management. Here, we utilized mass cytometry (CyTOF) to thoroughly phenotype peripheral myeloid cells and T lymphocytes from 30 convalescent patients with mild, moderate, and severe cases of COVID-19. We identified 10 clusters of monocytes and dendritic cells and 17 clusters of T cells. Examination of these clusters revealed that both CD14+CD16+ intermediate and CD14dimCD16+ nonclassical monocytes, as well as CD4+ stem cell memory T (TSCM) cells, correlated with COVID-19 severity, coagulation factor levels, and/or inflammatory indicators. We also identified two nonclassical monocyte subsets distinguished by expression of the sugar residue 6-Sulfo LacNac (Slan). One of these subsets (Slanlo, nMo1) was depleted in moderately and severely ill patients, while the other (Slanhi, nMo2) increased with disease severity and was linked to CD4+ T effector memory (TEM) cell frequencies, coagulation factors, and inflammatory indicators. Intermediate monocytes tightly correlated with loss of naive T cells as well as an increased abundance of effector memory T cells expressing the exhaustion marker PD-1. Our data suggest that both intermediate and non-classical monocyte subsets shape the adaptive immune response to SARS-CoV-2. In summary, our study provides both broad and in-depth characterization of immune cell phenotypes in response to COVID-19 and suggests functional interactions between distinct cell types during the disease. One Sentence SummaryUse of mass cytometry on peripheral blood mononuclear cells from convalescent COVID-19 patients allows correlation of distinct monocyte and T lymphocyte subsets with clinical factors.

immunology↗

bioRxiv2020

Spatially discrete signalling niches regulate fibroblast heterogeneity in human lung cancer

Fibroblasts are functionally heterogeneous cells, capable of promoting and suppressing tumour progression. Across cancer types, the extent and cause of this phenotypic diversity remains unknown. We used single-cell RNA sequencing and multiplexed immunohistochemistry to examine fibroblast heterogeneity in human lung and non-small cell lung cancer (NSCLC) samples. This identified seven fibroblast subpopulations: including inflammatory fibroblasts and myofibroblasts (representing terminal differentiation states), quiescent fibroblasts, proto-myofibroblasts (x2) and proto-inflammatory fibroblasts (x2). Fibroblast subpopulations were variably distributed throughout tissues but accumulated at discrete niches associated with differentiation status. Bioinformatics analyses suggested TGF-{beta}1 and IL-1 as key regulators of myofibroblastic and inflammatory differentiation respectively. However, in vitro analyses showed that whilst TGF-{beta}1 stimulation in combination with increased tissue tension could induce myofibroblast marker expression, it failed to fully re-capitulate ex-vivo phenotypes. Similarly, IL-1{beta} treatment only induced upregulation of a subset of inflammatory fibroblast marker genes. In silico modelling of ligand-receptor signalling identified additional pathways and cell interactions likely to be involved in fibroblast activation, which can be examined using publicly available R shiny applications (at the following links: myofibroblast activation and inflammatory fibroblast activation). This highlighted a potential role for IL-11 and IL-6 (among other ligands) in myofibroblast and inflammatory fibroblast activation respectively. This analysis provides valuable insight into fibroblast subtypes and differentiation mechanisms in NSCLC.

cancer biology↗