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bioRxiv2022

Rapid Rerouting of Myosin Traffic at the T Cell Immunological Synapse

Cytoskeletal motors travel in patterns set by the architecture of their tracks. Nevertheless, we have a limited understanding of how cells dynamically reorganize their traffic patterns in response to signaling events. To investigate cytoskeletal motor rerouting, we used T cells as a model system. Upon an encounter between a T cell and an antigen presenting cell, the T cell builds a specialized interface with spatially organized immunoreceptors and adhesion molecules called the immunological synapse (IS). The IS also constructs new actin networks within minutes that define the synaptic structure. Here we track the movements of single myosin motors along presynaptic and synaptic actin networks of the T cell. We find that both myosin-5 and myosin-6 reroute after IS construction. For example, most myosin-5 traffic moves inward at the IS, although most of the IS actin filaments have a barbed end out orientation. This anomalous myosin-5 traffic pattern indicates that the IS makes two types of actin networks: a structural network that controls IS shape, and a distinct trafficking network that supports myosin motility. We disrupt these trafficking networks with chemical probes against actin, which inhibits the appearance of cell surface markers of T cell activation. Our results highlight the importance of the sparse actin networks at the center of the IS in T cell function.

cell biology↗

bioRxiv2022

Immunological Synapse Dynamics Induced by Bispecific T-cell Engagers Predict Clinical Pharmacodynamics and Tumor Evolution across Anatomical Sites

Effector T cells form immunological synapses (IS) with recognized target cells to elicit cytolytic effects. Facilitating IS formation is the principal pharmacological action of most T cell-based cancer immunotherapies. However, the dynamics of IS formation at the cell population level, the primary driver of the pharmacodynamics of many cancer immunotherapies, remains poorly defined. With classic immunotherapy CD3/CD19 bispecific T cell engager (BiTE) as a model system, we integrate experimental and theoretical approaches to investigate the population dynamics of IS formation and their relevance to clinical pharmacodynamics and treatment resistance. Our models produce experimentally consistent predictions when defining IS formation as a series of spatiotemporally coordinated events driven by molecular and cellular interactions. The models predict tumor-killing pharmacodynamics in patients and reveal trajectories of tumor evolution across anatomical sites under BiTE immunotherapy. Our model highlight the bone marrow may serve as a sanctuary site permitting tumor evolution and antigen escape. The models also suggest the optimal dosing regimens as a function of tumor growth and patient T cell abundance that confer adequate tumor control with minimal disease evolution. This work has implications for developing more effective T cell-based cancer immunotherapies.

pharmacology and toxicology↗

bioRxiv2022

SARS-CoV-2 evolution and patient immunological history shape the breadth and potency of antibody-mediated immunity

Since the emergence of SARS-CoV-2, humans have been exposed to distinct SARS-CoV-2 antigens, either by infection with different variants, and/or vaccination. Population immunity is thus highly heterogeneous, but the impact of such heterogeneity on the effectiveness and breadth of the antibody-mediated response is unclear. We measured antibody-mediated neutralisation responses against SARS-CoV-2Wuhan, SARS-CoV-2, SARS-CoV-2{delta} and SARS-CoV-2o pseudoviruses using sera from patients with distinct immunological histories, including naive, vaccinated, infected with SARS-CoV-2Wuhan, SARS-CoV-2 or SARS-CoV-2{delta}, and vaccinated/infected individuals. We show that the breadth and potency of the antibody-mediated response is influenced by the number, the variant, and the nature (infection or vaccination) of exposures, and that individuals with mixed immunity acquired by vaccination and natural exposure exhibit the broadest and most potent responses. Our results suggest that the interplay between host immunity and SARS-CoV-2 evolution will shape the antigenicity and subsequent transmission dynamics of SARS-CoV-2, with important implications for future vaccine design. Author SummaryNeutralising antibodies provide protection against viruses and are generated because of vaccination or prior infections. The main target of anti-SARS-CoV-2 neutralising antibodies is a protein called Spike, which decorates the viral particle and mediates viral entry into cells. As SARS-CoV-2 evolves, mutations accumulate in the spike protein, allowing the virus to escape antibody-mediated immunity and decreasing vaccine effectiveness. Multiple SARS-CoV-2 variants have appeared since the start of the COVID-19 pandemic, causing various waves of infection through the population and infecting-in some cases-people that had been previously infected or vaccinated. Since the antibody response is highly specific, individuals infected with different variants are likely to have different repertoires of neutralising antibodies. We studied the breadth and potency of the antibody-mediated response against different SARS-CoV-2 variants using sera from vaccinated people as well as from people infected with different variants. We show that potency of the antibody response against different SARS-CoV-2 variants depends on the particular variant that infected each person, the exposure type (infection or vaccination) and the number and order of exposures. Our study provides insight into the interplay between virus evolution and immunity, as well as important information for the development of better vaccination strategies.

microbiology↗

bioRxiv2022

Immunological contributions to age-dependent variations in behavioural responses to cutaneous inflammation

Systemic responses to immune challenge are immature at birth. However exposure to experimental inflammogens are able to produce an immunologic response which is characterised by swelling and oedema but, unlike in adults, does not result in sensory hypersensitivity. We sought to investigate whether the lack of nociceptive hypersensitivity was as a result of altered hemapoietic immune cell recruitment to the site of inflammation and/or differences in the cytokine and chemokine profile released by tissue invading cells. Postnatal (day of birth) and young adult (40-days old) Sprague-Dawley rats were used. Inflammation was induced by s.c. injection of Complete Freunds Adjuvant (CFA) unilaterally into the one hind paw. Mechanical withdrawal thresholds were measured before and after injection (2-168hrs). In adults a significant hyperalgesia was evoked which was absent in neonates. Immunohistochemical analysis of invading immune cells present in the perfusion fixed skin showed that although total cell numbers in the paw were the same in both age groups, neonates recruited more cells positive for both cell surface markers CD68 and Mannose-receptor (MR) whereas adults recruited significantly more cells positive for MR alone. There were no differences in neutrophil recruitment (as measured with H&E staining). TaqMan qPCR demonstrated that the temporal profile of cytokine production in the skin differed between ages with neonates responding faster than adults and that neonates produced significantly more IL-1b and IL-27 then adults who expressed significantly more IL-6 and IL-10. This study illustrates that in neonates the cell recruitment and cytokine profiles are markedly different to those seen in adults; this may in part explain why behavioural responses to inflammation are suppressed relative to adults.

neuroscience↗

bioRxiv2022

Polymorphic regions in BA.2.12.1, BA.4 and BA.5 likely implicated in immunological evasion of Omicron subvariant BQ.1.1

In this work, 45 Spike glycoprotein Chain B polypeptides were used in the subvariants BA.2.12.1, BA.4 and BA.5 were recovered from GENBANK. All sequences were publicly available on the National Biotechnology Information Center (NCBI) platform. The results indicate the existence of informative polymorphic and parsimony sites that may be implicated in the level of diversity of the studied strains, as well as reflect the immunological evasion potential of the subvariant BQ1.1. of the variant Omicron d and SARS-CoV-2. The results also suggest the formation of ancestral polymorphism with slight retention, and the probable is responsible the diversity of the whole studied set.

bioinformatics↗

bioRxiv2023

Post-acute immunological and behavioral sequelae in mice after Omicron infection

Progress in understanding long COVID and developing effective therapeutics is hampered in part by the lack of suitable animal models. Here we used ACE2-transgenic mice recovered from Omicron (BA.1) infection to test for pulmonary and behavioral post-acute sequelae. Through in-depth phenotyping by CyTOF, we demonstrate that naive mice experiencing a first Omicron infection exhibit profound immune perturbations in the lung after resolving acute infection. This is not observed if mice were first vaccinated with spike-encoding mRNA. The protective effects of vaccination against post-acute sequelae were associated with a highly polyfunctional SARS-CoV-2-specific T cell response that was recalled upon BA.1 breakthrough infection but not seen with BA.1 infection alone. Without vaccination, the chemokine receptor CXCR4 was uniquely upregulated on multiple pulmonary immune subsets in the BA.1 convalescent mice, a process previously connected to severe COVID-19. Taking advantage of recent developments in machine learning and computer vision, we demonstrate that BA.1 convalescent mice exhibited spontaneous behavioral changes, emotional alterations, and cognitive-related deficits in context habituation. Collectively, our data identify immunological and behavioral post-acute sequelae after Omicron infection and uncover a protective effect of vaccination against post-acute pulmonary immune perturbations.

microbiology↗

bioRxiv2023

Machine learning approaches identify immunologic signatures of total and intact HIV DNA during long-term antiretroviral therapy.

Understanding the interplay between the HIV reservoir and the host immune system may yield insights into HIV persistence during antiretroviral therapy (ART) and inform strategies for a cure. Here, we applied machine learning approaches to cross-sectional high-parameter HIV reservoir and immunology data in order to characterize host-reservoir associations and generate new hypotheses about HIV reservoir biology. High-dimensional immunophenotyping, quantification of HIV-specific T cell responses, and measurement of genetically intact and total HIV proviral DNA frequencies were performed on peripheral blood samples from 115 people with HIV (PWH) on long-term ART. Analysis demonstrated that both intact and total proviral DNA frequencies were positively correlated with T cell activation and exhaustion. Years of ART and select bifunctional HIV-specific CD4 T cell responses were negatively correlated with the percentage of intact proviruses. A Leave-One-Covariate-Out (LOCO) inference approach identified specific HIV reservoir and clinical-demographic parameters, such as age and biological sex, that were particularly important in predicting immunophenotypes. Overall, immune parameters were more strongly associated with total HIV proviral frequencies than intact proviral frequencies. Uniquely, however, expression of the IL-7 receptor alpha chain (CD127) on CD4 T cells was more strongly correlated with the intact reservoir. Unsupervised dimension reduction analysis identified two main clusters of PWH with distinct immune and reservoir characteristics. Using reservoir correlates identified in these initial analyses, decision tree methods were employed to visualize relationships among multiple immune and clinical-demographic parameters and the HIV reservoir. Finally, using random splits of our data as training-test sets, machine learning algorithms predicted with approximately 70% accuracy whether a given participant had qualitatively high or low levels of total or intact HIV DNA. The techniques described here may be useful for assessing global patterns within the increasingly high-dimensional data used in HIV reservoir and other studies of complex biology.

microbiology↗

bioRxiv2023

An Immunological Synapse Formation Between T Regulatory Cells and Cancer-Associated Fibroblasts Promotes Tumor Development

Cancer-associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumor microenvironment, serving diverse functions in tumor progression, invasion, matrix remodeling and resistance to therapy; yet, the precise mechanisms via which CAFs imprint on the anti-tumor immunity remain poorly understood. Extensive molecular characterization revealed an increased heterogeneity in the CAF compartment and proposed an interaction between CAFs and tumor-infiltrating immune cells, which may shape tumor immune evasion. Herein, we describe a synapse formation between -SMA+ CAFs and regulatory T cells (Tregs) in the TME. Foxp3+ Tregs were localized close to -SMA+ CAFs in diverse types of tumor models as well as biopsies from melanoma and colorectal cancer patients. Notably, phenotypically tolerogenic -SMA+ CAFs demonstrated the ability to phagocytose and process tumor antigens, instructing Treg movement arrest, activation and proliferation, in an antigen-specific manner. Of interest, -SMA+ CAFs were characterized by the presence of double-membrane structures, resembling autophagosomes, in their cytoplasm, while analysis of single-cell transcriptomic data pointed autophagy and antigen processing/presentation pathways to be enriched in -SMA-expressing CAF clusters. In a mechanistic view, conditional knockout of the autophagy pathway in -SMA+ CAFs promoted an inflammatory re-programming of CAFs, reduced Treg infiltration, attenuated tumor development, and potentiated the efficacy of immune checkpoint inhibitor immunotherapy. Overall, our findings reveal an immunosuppressive mechanism operating in the TME, which entails the formation of synapses between -SMA+ CAFs and Tregs in an autophagy-dependent fashion and raises the potential for the development of CAF-targeted therapies in cancer. One Sentence Summary-SMA+ Cancer Associated Fibroblasts process and present tumor antigens via autophagy to form immunological synapses with Foxp3+ T regulatory cells in the tumor microenvironment, promoting tumor development.

cancer biology↗

bioRxiv2024

Intraspecific venom variation in the medically important puff adder (Bitis arietans): comparative venom gland transcriptomics, in vitro venom activity and immunological recognition by antivenom

BackgroundVariation in snake venoms is well documented, both between and within species, with intraspecific venom variation often correlated with geographically distinct populations. The puff adder, Bitis arietans, is found widely distributed across sub-Saharan Africa and into the Arabian Peninsula where it is considered a leading cause of the [~]310,000 annual snakebites across the region, with its venom capable of causing substantial morbidity and mortality. Despite its medical importance and wide geographic distribution, there is little known about venom variation between different B. arietans populations and the potential implications of this variation on antivenom efficacy. MethodologyWe applied a range of analyses, including venom gland transcriptomics, in vitro enzymatic assays and reverse phase chromatography to comparatively analyse B. arietans venoms originating from Nigeria, Tanzania, and South Africa. Immunological assays and in vitro enzymatic neutralisation assays were then applied to investigate the impact of venom variation on the potential efficacy of three antivenom products; SAIMR Polyvalent, EchiTAb-Plus and Fav-Afrique. FindingsThrough the first comparison of venom gland transcriptomes of B. arietans from three geographically distinct regions (Nigeria, Tanzania, and South Africa), we identified substantial variation in toxin expression. Findings of venom variation were further supported by chromatographic venom profiling, and the application of enzymatic assays to quantify the activity of three pathologically relevant toxin families. However, the use of western blotting, ELISA, and in vitro enzymatic inhibition assays revealed that variation within B. arietans venom does not appear to substantially impact upon the efficacy of three African polyvalent antivenoms. ConclusionsThe large distribution and medical importance of B. arietans makes this species ideal for understanding venom variation and the impact this has on therapeutic efficacy. The findings in this study highlight the likelihood for considerable venom toxin variation across the range of B. arietans, but that this may not dramatically impact upon the utility of treatment available in the region. Author SummaryThe puff adder (Bitis arietans) is found across sub-Saharan Africa and the Arabian Peninsula and is capable of causing life threatening pathology due to its potent venom. The extensive range of B. arietans exposes populations to different ecological pressures which may impact upon the composition of venom toxins. In this study, we examined the venom composition of B. arietans from three countries separated by large geographic distance: Nigeria, Tanzanian and South Africa. By integrating venom gland transcriptomes, venom chromatography, and in vitro functional assays to profile B. arietans venom composition, we uncovered extensive variation between the three locales. Given that venom variation can have a significant impact on the efficacy of antivenom treatment, we also investigated the ability of three African antivenoms to recognise and inhibit in vitro venom activity. Through these analyses, we were able to determine that venom variation did not have a substantial impact on the neutralising effect of selected antivenoms. This study has highlighted the potentially extensive venom variation found across the range of B. arietans and initiated valuable investigations into the efficacy of African antivenoms to protect human populations vulnerable to snakebite envenoming.

molecular biology↗

bioRxiv2024

Extracellular vesicles produced during fungal infection in humans are immunologically active

Of the known 1.5 million fungal species, Candida spp., Cryptococcus spp., and Paracoccidioides spp. are the main pathogenic species causing serious diseases with almost two million annual deaths. The diagnosis and treatment of fungal infections are challenging since of the limited access to diagnostic tests and the emergence of antifungal resistance. Extracellular vesicles (EVs) promote the interactions of fungal cells with other organisms and play an important role in the pathogen-host relationship. Owing to the complexity of fungal EVs and the lack of clinical studies on their roles in human infections, we studied the EVs from the serum and urine samples of patients with fungal infections caused by Candida albicans, Cryptococcus neoformans, and Paracoccidioides brasiliensis and determined their roles. Steroids, sphingolipids, and fatty acids were identified as the main secondary metabolites via mass spectrometry analysis. We asked whether these metabolites in EVs could play roles in modulating the host immune response. Our findings revealed the polarization of the proinflammatory profile in murine and human macrophages, with the increased production of cytokines, such as the tumor necrosis factor-, interferon-{gamma}, and interleukin-6, and an increased expression of the inducible nitric oxide synthase gene, a M1 response marker. Therefore, circulating EVs from patients with fungal infections are likely involved in the disease pathophysiology. Our findings provide insights into the roles of EVs in fungal infections in clinical samples and in vitro, suggesting possible targets for systemic mycoses therapy. Significance StatementFungal infections cause approximately 1.6 million deaths annually. Due to therapeutic and diagnostic limitations, it is mandatory to understand and develop new immunological interventions. Despite several in vitro studies on the production of extracellular vesicles (EVs) from fungal pathogens, this study is a pioneer in the identification and characterization of EVs in the course of fungal infection in humans. Our group demonstrated the presence of EVs in clinical samples from patients diagnosed with candidiasis, cryptococcosis, and paracoccidioidomycosis, as well as the EVs interaction produced by host and fungal pathogen with the immune system, resulting in relationships that may be beneficial for the progression or elimination of fungal disease.

microbiology↗

bioRxiv2024

Pulmonary granuloma formation during latent Cryptococcus neoformans infection in C3HeB/FeJ mice involves progression through three immunological phases

Cryptococcus neoformans is a fungal pathogen that can cause lethal disease in immunocompromised patients. Immunocompetent host immune responses, such as formation of pulmonary granulomas, control the infection and prevent disseminated disease. Little is known about the immunological conditions establishing the latent infection granuloma in the lungs. To investigate this, we performed an analysis of pulmonary immune cell populations, cytokine changes, and granuloma formation during infection with a latent disease-causing clinical isolate in C3HeB/FeJ mice over 360 days. We found that latently infected mice progress through three phases of granuloma formation where different immune profiles dominate: an early phase characterized by eosinophilia, high IL-4/IL-13, and C. neoformans proliferation in the lungs; an intermediate phase characterized by multinucleated giant cell formation, high IL-1/IFN{gamma}, granuloma expansion, and increased blood antigen levels; and a late phase characterized by a significant expansion of T cells, granuloma condensation, and decreases in lung fungal burden and blood antigen levels. These findings highlight a complex series of immune changes that occur during the establishment of granulomas that control C. neoformans in the lungs and lay the foundation for studies to identify critical beneficial immune responses to Cryptococcus infections. IMPORTANCECryptococcus neoformans is a fungal pathogen that disseminates from the lungs to the brain to cause fatal disease. Latent C. neoformans infection in the lungs is controlled by organized collections of immune cells called granulomas. The formation and structure of Cryptococcus granulomas are poorly understood due to inconsistent human pathology results and disagreement between necrotic granuloma-forming rat models and non-necrotic granuloma-forming mouse models. To overcome this, we investigated granuloma formation during latent C. neoformans infection in the C3HeB/FeJ mouse strain which forms necrotic lung granulomas in response to other pathogens. We found that latent C. neoformans granuloma formation progresses through phases that we described as early, intermediate, and late with different immune response profiles and granulomatous characteristics. Ultimately, we show that C3HeB/FeJ mice latently infected with C. neoformans form non-necrotic granulomas and could provide a novel mouse model to investigate host immune response profiles.

microbiology↗

bioRxiv2025

Single-cell RNA sequencing of peripheral blood defines two immunological subtypes of Sjögren's disease

Sjogrens disease (SjD) is a heterogeneous autoimmune disorder with significant clinical and molecular diversity. While anti-SSA antibodies serve as a hallmark serological biomarker, nearly half of patients lack them, raising fundamental questions about distinct pathogenic mechanisms. To address this, we performed single-cell RNA sequencing with surface protein profiling on 1.5 million PBMCs from 333 participants in the Sjogrens International Collaborative Clinical Alliance cohort, comparing those with and without SjD and stratifying them by anti-SSA status. Our analysis identified two immunologically distinct subtypes of SjD, with SSA-positive patients exhibiting a dominant and persistent IFN-I signature, profoundly impacting immune cell maturation. Notably, transitional B cells were disproportionately affected, displaying signs of premature maturation, reduced BCR diversity, and shorter CDR3 regions, reinforced interactions with proinflammatory cells, thereby fostering an environment conducive to autoreactivity. By contrast, SSA-negative SjD participants lacked an upregulated IFN-I signature, challenging prevailing pathogenic models and suggesting alternative immune dysregulation pathways. These findings support a two-disease model of SjD and highlight transitional B cells as both a key biomarker and a potential therapeutic target. Targeting IFN-I signaling and transitional B cell maturation may represent a novel therapeutic avenue to modulate immune dysregulation and prevent autoreactivity in SjD.

genomics↗

bioRxiv2025

The CXCL10/CXCR3 axis is essential for sustaining immunological dormancy in breast cancer

Immune surveillance plays a pivotal role in controlling tumor emergence, dormancy and progression, including in breast cancer. Despite its potential clinical relevance, the mechanisms governing dormancy initiation, maintenance and escape, as well as the molecular mediators involved, remain poorly understood. Here, we identify the interferon-inducible chemokine CXCL10 and its receptor CXCR3 as key regulators of immunological dormancy in breast cancer. By transcriptomic profiling we observed high expression of Cxcl10 in dormant cells in two different orthotopic, syngeneic models of breast cancer dormancy (D2.0R and 4T1-MR20). Genetic silencing of Cxcl10 in dormant cells or pharmacological blockade of CXCR3 in vivo, led to early tumor onset and rapid growth in immunocompetent mice. In contrast dormant cells effectively formed tumors in immune-deficient mice independently of Cxcl10 status, demonstrating that the CXCL10/CXCR3 axis-mediated dormancy requires a functional immune system. Further analysis confirmed that Cxcl10 silencing altered the local immune microenvironment, reducing CD4+ and CD8+ T cell infiltration while increasing the presence of granulocytic Myeloid Derived Suppressor Cells and Natural Killer cells. Moreover, Cxcl10 silencing significantly increased the burden of tumor cells disseminated to the lung. Leveraging on these findings, we identified a CXCL10-mediated dormancy signature that predicts improved overall survival in triple-negative breast cancer (TNBC) patients. Our findings have identified a new mechanism modulating breast cancer dormancy with important clinical implications: the CXCL10/CXCR3 axis as a potential therapeutic target for improving survival of patients with TNBC, and the CXCL10-dependent dormancy signature as a tool for identifying these patients.

cancer biology↗

bioRxiv2025

Gonadal Hormone Status Dictates Neurobehavioral, Metabolic and Immunological Benefits of Ketogenic Diet in Female Mice through Gut-Metabolic-Brain Axis

The ketogenic diet (KD) is recognized for its broad therapeutic potential across metabolic, neurological, immunological, and aging-related domains; however, its efficacy and durability in females remain underexplored. This study investigated the effects of a short-term, intermittent KD on neurobehavioral function, lipid metabolism, immune response, and gut microbiota composition in sham-operated (intact) and ovariectomized (OVX, estrogen-deficient) female mice, aiming to delineate the interactions between diet and gonadal hormones. In sham females, KD reduced circulating estradiol levels and induced low-grade systemic inflammation, without producing measurable behavioral benefits. Conversely, KD exhibited reduced compulsivity, anxiety, and depression-like behaviors with improved well-being in OVX females, suggesting enhanced neurobehavioral resilience under estrogen-deficient conditions. Biochemical analyses revealed KD-induced hyperlipidemia in both groups, although the lipid load was attenuated in OVX mice. KD further decreased low-density lipoprotein cholesterol but led to uremia and histopathological evidence of hepatic steatosis and fibrosis in OVX females, despite unaltered liver function markers. 16S rRNA sequencing revealed hormone-dependent remodelling of the gut microbiota, characterised by distinct compositional shifts between the sham and OVX cohorts. Correlation analyses linked microbial alterations to improved lipid profiles and reduced anxiodepressive behaviors, implicating the gut-metabolic-brain axis in mediating the effects of KD. Collectively, these findings suggest that KD confers neurobehavioral and metabolic benefits in the absence of ovarian hormones but may also pose risks to the liver and kidneys. These results highlight ketogenic nutrition as a potential non-pharmacological strategy to mitigate menopause- and aging-associated neurobehavioral, metabolic, and immune dysfunctions through modulation of the gut microbiota.

neuroscience↗

bioRxiv2017

A Comprehensive Immunologic Portrait of Triple-Negative Breast Cancer

BackgroundTriple-negative breast cancer (TNBC) is a high-risk malignancy due to its high capacity for invasion and lack of targeted therapy. Immunotherapy continues to demonstrate efficacy in a variety of cancers, and thus may be a promising strategy for TNBC given the limited therapeutic options currently available for TNBC. In this study, we performed a comprehensive portrait of immunologic landscape of TNBC based on 2 large-scale breast cancer genomic data.\n\nMethodsWe compared expression levels of immune-related genes and gene-sets among TNBC, non-TNBC, and normal tissue, and within TNBCs of different genotypic or phenotypic features. Moreover, we explored the association of immune-related genes or gene-sets expression and survival prognosis in TNBC patients.\n\nResultsWe found that almost all analyzed immune-related gene-sets had significantly higher expression levels in TNBC than non-TNBC. These highly expressed gene-sets in TNBC included 15 immune cell type and function, human leukocyte antigen (HLA), cancer testis (CT), tumor-infiltrating lymphocytes (TILs), immune cell infiltrate, regulatory T (Treg) cells, immune checkpoint, cytokine and cytokine receptor, metastasis-promoting, pro-inflammatory and parainflammation (PI) gene-sets. Moreover, TP53-mutated, TNBC had significantly higher expression levels of the immune checkpoint, Treg, PI, and CT gene-sets, and lower expression levels of the immune cell infiltrate gene-set than TP53-wildtype TNBC. Furthermore, we found that elevated expression of most of the immune-related genes in TNBC was associated with the ER-status, while some were associated with both ER-and HER2-status. Elevated expression of the immune-related genes in TNBC was also associated with the high tumor mutation burden (TMB) in TNBC. Finally, elevated expression of the immune-related gene-sets was likely to be associated with better survival prognosis in TNBC.\n\nConclusionsOur findings suggest that TNBC is a breast cancer subtype with particularly strong immunogenicity, and therefore could be propitious to immunotherapeutic options.

cancer biology↗

bioRxiv2018

CytoBinning: immunological insights from multi-dimensional data

New cytometric techniques continue to push the boundaries of multi-parameter quantitative data acquisition at the single-cell level particularly in immunology and medicine. Sophisticated analysis methods for such ever higher dimensional datasets are rapidly emerging, with advanced data representations and dimensional reduction approaches. However, these are not yet standardized and clinical scientists and cell biologists are not yet experienced in their interpretation. More fundamentally their range of statistical validity is not yet fully established. We therefore propose a new method for the automated and unbiased analysis of high-dimensional single cell datasets that is simple and robust, with the goal of reducing this complex information into a familiar 2D scatter plot representation that is of immediate utility to a range of biomedical and clinical settings. Using publicly available flow cytometry and mass cytometry datasets we demonstrate that this method (termed CytoBinning), recapitulates the results of traditional manual cytometric analyses and leads to new and testable hypotheses.

bioinformatics↗

bioRxiv2018

Cytoskeletal tension actively sustains the T cell immunological synapse

When migratory T cells encounter antigen presenting cells (APCs), they arrest and form radially symmetric, stable intercellular junctions termed immunological synapses which facilitate exchange of crucial biochemical information and are critical for T cell immunity. While the cellular processes underlying synapse formation have been well-characterized, those that maintain the symmetry, and thereby the stability of the synapse remain unknown. Here we identify an antigen-triggered mechanism that actively promotes T cell synapse symmetry by generating cytoskeletal tension in the plane of the synapse through focal nucleation of actin via Wiskott -Aldrich syndrome Protein (WASP), and contraction of the resultant actin filaments by myosin II. Following T cell activation, WASP is degraded, leading to cytoskeletal rearrangement and tension decay, which result in synapse breaking. Thus, our study identifies and characterizes a mechanical program within otherwise highly motile T cells that sustains the symmetry and stability of the T cell-APC synaptic contact.

cell biology↗

bioRxiv2018

To cure or not to cure: consequences of immunological interactions in CML treatment

Recent clinical findings in Chronic Myeloid Leukemia (CML) patients suggest that the number and function of immune effector cells are modulated by Tyrosine Kinase Inhibitors (TKI) treatment. There is further evidence that the success or failure of treatment cessation at least partly depends on the patients immunological constitution. Here, we propose a general ODE model to functionally describe the interactions between immune effector cells with leukemic cells during the TKI treatment of CML. In total, we consider 20 different sub-models, which assume different functional interactions between immune effector and leukemic cells. We show that quantitative criteria, which are purely based on the quality of model fitting, are not able to identify optimal models. On the other hand, the application of qualitative criteria based on a dynamical system framework allowed us to identify nine of those models as more suitable than the others to describe clinically observed patterns and, thereby, to derive conclusion about the underlying mechanisms. Additionally, including aspects of early CML onset, we can demonstrate that certain critical parameters, such as the strength of immune response or leukemia proliferation rate, need to change during CML growth prior to diagnosis, leading to bifurcations that alter the attractor landscape. Finally, we show that the crucial parameters determining the outcome of treatment cessation are not identifiable with tumor load data only, thereby highlighting the need to measure immune cell number and function to properly derive mathematical models with predictive power.

systems biology↗