Biology subjects

Halasz, L.

Publications and source records attributed to Halasz, L..

8 recordsLinked to original sources

bioRxiv2025

TREM2 macrophages are associated with enhanced response to PD-1 blockade in human hepatocellular carcinoma

Macrophages are known to dampen tumor immunity. However, identifying druggable targets that modulate these cells to improve existing immunotherapies has been limited by a dearth of studies identifying macrophages that associate with pathological response to immune checkpoint blockade. To fulfill this unmet clinical need, we leveraged transcriptional and spatial profiling of specimens collected from a Phase II clinical trial studying neoadjuvant PD-1 blockade in patients with hepatocellular carcinoma (HCC). We determined that the intratumoral abundance of TREM2-expressing macrophages and serological levels of soluble TREM2 are elevated in patients who responded to PD-1 blockade, compared to non-responders. We validated these findings in a second HCC cohort and in the IMbrave150 trial. These highlight the robust potential for TREM2 macrophages to predict therapeutic responses of HCC to immunotherapy. Therefore, our study provides a novel basis for the use of TREM2 macrophages to strategize treatment for patients with HCC to maximize therapeutic benefit.

immunology↗

bioRxiv2025

Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms

"Trained immunity" of innate immune cells occurs through a sequential two-step process where an initial pathogenic or sterile inflammatory trigger is followed by an amplified response to a later un-related secondary pathogen challenge. The memory effect is mediated at least in part through epigenetic modifications of the chromatin landscape. Here, we investigated the role of the epigenetic modifier Setdb2 in microbial ({beta}-glucan) or sterile trigger (Western-diet-WD/oxidized-LDL-oxLDL)-induced trained immunity of macrophages. Using genetic mouse models and genomic analysis, we uncovered a critical role of Setdb2 in regulating proinflammatory and metabolic pathway reprogramming. We further show that Setdb2 regulates trained immunity through two different complementary mechanisms: one where it positively regulates glycolytic and inflammatory pathway genes via enhancer-promoter looping, and is independent of its enzymatic activity; while the second mechanism is associated with both increased promoter associated H3K9 methylation and repression of interferon response pathway genes. Interestingly, while both mechanisms occur in response to pathogenic training, only the chromatin-looping mechanism operates in response to the sterile inflammatory stimulus. These results reveal a previously unknown bifurcation in the downstream pathways that distinguishes between pathogenic and sterile inflammatory signaling responses associated with the innate immune memory response and may provide potential therapeutic opportunities to target cytokine vs. interferon pathways to limit complications of chronic inflammation.

immunology↗

bioRxiv2024

Dendritic cells type 1 control the formation, maintenance, and function of tertiary lymphoidstructures in cancer

Tertiary lymphoid structures (TLS) are organized immune cell aggregates that arise in chronic inflammatory conditions. In cancer, TLS are associated with better prognosis and enhanced response to immunotherapy, making these structures attractive therapeutic targets. However, the mechanisms regulating TLS formation and maintenance in cancer are incompletely understood. Using spatial transcriptomics and multiplex imaging across various human tumors, we found an enrichment of mature dendritic cells (DC) expressing high levels of CCR7 in TLS, prompting us to investigate the role of DC in the formation and maintenance of TLS in solid tumors. To address this, we developed a novel murine model of non-small cell lung cancer (NSCLC) that forms mature TLS, containing B cell follicles with germinal centers and T cell zones with T follicular helper cells (TFH) and TCF1+PD-1+ progenitor exhausted CD8+ T cells (Tpex). Here we show that, during the early stages of tumor development, TLS formation relies on IFN{gamma}-driven maturation of the conventional DC type 1 (cDC1) subset, their migration to tumor-draining lymph nodes (tdLN), and recruitment of activated T cells to the tumor site. As tumors progress, TLS maintenance becomes independent of T cell egress from tdLN, coinciding with a significant reduction of cDC1 migration to tdLN. Instead, mature cDC1 accumulate within intratumoral CCR7 ligand-enriched stromal hubs. Notably, timed depletion of cDC1 or disruption of their migration to these stromal hubs after TLS are formed alters TLS maintenance. Importantly, we found that cDC1-mediated antigen presentation to both CD4+ and CD8+ T cells and intact CD40 signaling, is critical for the maintenance of TLS, the preservation of the TFH cell pool, the formation of germinal center and the production of tumor-specific IgG antibodies. These findings underscore the key role of mature cDC1 in establishing and maintaining functional TLS within tumor lesions and highlight the potential for cDC1-targeting therapies as a promising strategy to enhance TLS function and improve anti-tumor immunity in patients with cancer.

immunology↗

bioRxiv2024

Dendritic cells accelerate CAR T cells in irradiated tumors through chimeric synapses

The persistence of adoptively transferred T cells is vital for anti-tumor efficacy. Chimeric antigen receptor (CAR) T cells can persist indefinitely when delivered to patients with B cell cancers and can confer long-term remission. For patients with solid tumors, however, sustaining CAR T cell activity remains a major challenge. This has been attributed in part to the immune microenvironment within solid tumors, though the contribution of specific immune subsets to resistance to CAR T cells is not clear. Here we resolve how the immunology of irradiated tumors dramatically enhances persistence and efficacy of CAR T cells targeted to advanced lung metastases in a syngeneic mouse model. Remarkably, CAR T cell persistence depended critically on dendritic cells (DC) that underwent trogocytic "antigen-dressing" of tumor target antigens and stimulated CAR T cells through the chimeric receptor. Furthermore, tumor irradiation increased antigen-dressing onto DCs. In the absence of functional DCs, CAR T cell activity in irradiated tumor was short-lived and tumors relapsed. These findings establish a critical mechanism through which DCs maintain the CAR T cell pool in irradiated tumors, thus supporting translation of this approach to advance CAR T cell therapy for solid tumors.

immunology↗

bioRxiv2024

Heartbeat related activity in the anterior thalamus differs between phasic and tonic REM sleep periods

Rapid eye movement (REM) sleep is a fundamental sleep state associated with diverse functions from elemental physiological processes to higher order neurocognitive functions. A growing body of research indicates that REM sleep with eye movements (phasic REM) differs from REM periods without ocular activity (tonic) in terms of spontaneous and evoked neural responses. Studies using auditory stimulation consistently observed enhanced evoked responses in tonic versus phasic REM, indicating that the external processing is largely diminished when the eyes move during REM sleep. Whereas exteroceptive processing during sleep is widely studies, investigation on interoception (the processing of bodily signals) during sleep is scarce, and limited to scalp electroencephalographic recordings. Here we studied interoceptive processing in a group of epileptic patients (N = 11) by measuring their heartbeat-related neural activity in the anterior nucleus of the thalamus (ANT) during phasic and tonic REM sleep and resting wakefulness. Evoked potentials and beta-low gamma spectral power locked to the heartbeat were significantly different in phasic REM compared to tonic REM and wakefulness. Heartbeat-related neural signals exhibited pronounced inter-trial phase synchronization at lower (7-20 Hz) oscillatory activity in all vigilance states, but reduced gamma synchronization at later time points in phasic REM only. Tonic REM and wakefulness did not show significant differences in heartbeat-related activity in the ANT. Our findings indicate that heartbeat-related neural activity is detectable at the level of the ANT, showing distinct signatures of interoceptive processing in phasic REM compared to tonic REM and wakefulness.

neuroscience↗

bioRxiv2024

Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors

ABSTRACTMonocyte-derived macrophages (mo-macs) drive immunosuppression in the tumor microenvironment (TME) and tumor-enhanced myelopoiesis in the bone marrow (BM) fuels these populations. Here, we performed paired transcriptome and chromatin analysis over the continuum of BM myeloid progenitors, circulating monocytes, and tumor-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. Analyzing chromatin accessibility and histone mark changes, we show that lung tumors prime accessibility for Nfe2l2 (NRF2) in BM myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increased during monocyte differentiation into mo-macs in the lung TME to regulate oxidative stress, in turn promoting metabolic adaptation, resistance to cell death, and contributing to immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-macs survival and immunosuppression in the TME, enabling NK and T cell therapeutic antitumor immunity and synergizing with checkpoint blockade strategies. Altogether, our study identifies a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the TME.

immunology↗

bioRxiv2024

Epigenomic programming of peripheral monocytes determines their transcriptional response to the tumor microenvironment

Classical monocytes are recruited to tumors and undergo transcriptional reprogramming resulting in tumor-promoting functions. Epigenomic features, such as post-translational modification of histones and chromatin accessibility, are key determinants of transcription factor binding and thereby play an important role in determining transcriptional responses to the tissue environment. It is unknown to what extent the epigenetic landscape of peripheral monocytes is rewired by cancer and how this could shape their transcriptional response upon recruitment to the tumor microenvironment. Here we used a combination of genome-wide assays for mRNA expression, chromatin accessibility and multiple histone modifications (H3K4me1, H3K4me3, H3K27ac) in a mouse model to investigate changes in the epigenomic landscape of peripheral monocytes. We then linked these epigenetic alterations to gene expression changes in monocytes occurring in the periphery or during tumor infiltration. We found that the distal tumor caused extensive remodeling of both H3K4me3+ promoters and H3K4me1+ enhancers in peripheral monocytes. Specifically, this involved the repression of interferon-responsive promoters and enhancers as well as the establishment of enhancers harboring binding motifs for transcription factors downstream of inflammatory and cytokine signaling pathways. The enhancers altered in the periphery could be linked to sustained gene expression changes which were less likely to be reversed in the tumor microenvironment. In addition, genes activated upon tumor infiltration showed prior epigenetic priming in peripheral monocytes. Overall, these results indicate that the epigenomic landscape of peripheral monocytes is altered in response to a distal tumor, and this could shape the transcriptional response of monocytes when they encounter microenvironmental signals upon infiltrating the tumor.

immunology↗

bioRxiv2021

Sleep spindles, ripples, and interictal epileptiform discharges in the human anterior and mediodorsal thalamus

Sleep spindles are major oscillatory components of Non-Rapid Eye Movement (NREM) sleep, reflecting hyperpolarization-rebound sequences of thalamocortical neurons, the inhibition of which is caused by the NREM-dependent activation of GABAergic neurons in the reticular thalamic nucleus. Reports suggest a link between sleep spindles and several forms of interictal epileptic discharges (IEDs) which are considered as expressions of pathological off-line neural plasticity in the central nervous system. Here we investigated the relationship between thalamic sleep spindles, IEDs and ripples in the anterior and mediodorsal nuclei (ANT and MD) of epilepsy patients. Whole-night LFP from the ANT and MD were co-registered with scalp EEG/polysomnography by using externalized leads in 15 epilepsy patients undergoing Deep Brain Stimulation protocol. Slow ([~]12 Hz) and fast ([~]14 Hz) sleep spindles were present in the human ANT and MD. Roughly, one third of thalamic sleep spindles were associated with IEDs or ripples. Both IED- and ripple-associated spindles were longer than pure spindles. IED-associated thalamic sleep spindles were characterized by broadband increase in thalamic and cortical activity, both below and above the spindle frequency range, whereas ripple-associated thalamic spindles exceeded pure spindles in terms of 80-200 Hz thalamic, but not cortical activity as indicated by time-frequency analysis. These result show that thalamic spindles coupled with IEDs are reflected at the scalp slow and beta-gamma oscillation as well. IED density during sleep spindles in the MD, but not in the ANT was identified as correlates of years spent with epilepsy, whereas no signs of pathological processes were correlated with measures of ripple and spindle association. Furthermore, the density of ripple-associated sleep spindles in the ANT showed a positive correlation with general intelligence. Our findings indicate the complex and multifaceted role of the human thalamus in sleep spindle-related physiological and pathological neural plasticity.

neuroscience↗