Browse Articles

Frailty-Associated Immune Aging Signatures characterized by SASP and T Cell Effector Function Profiling 2258858

Abstract Introduction Immunosenescence contributes to infection risk, poor vaccine response, and chronic inflammation in older adults. Because chronological age does not reflect biological variability, clinical frailty offers a functional measure of physiological aging. Using the Korean Frailty Index (K-Frail), this study investigated frailty-associated immune signatures through integrated analyses of systemic inflammation and T cell profiles. Methods Peripheral blood was collected from young, healthy-, and frail-aged donors classified by K-Frail. PBMCs and plasma were analyzed for cellular and soluble immune factors. Multicolor flow cytometry assessed T cell subsets, senescence markers, and cytokine production. Plasma senescence-associated secretory phenotype (SASP) factors were quantified using a Luminex assay. Results Aging was characterized by reduced naïve and increased memory T cells with higher senescence marker expression. These phenotypic changes were comparable between healthy-aged and frail-aged groups, indicating limited additional T cell remodeling with frailty. However, functional assays revealed elevated frequencies of TNF-producing, polyfunctional CD8+ T cells (IFN-γ+MIP-1β+TNF+) in frail individuals. Systemic profiling identified a TNF-centered SASP network involving TNFR1, TNF-α, and IL-6, which was upregulated in frailty. TNFR1 levels and frequencies of polyfunctional CD8+ T cells correlated positively with K-Frail scores, linking TNF-associated inflammatory activity to frailty severity. Conclusion Frailty does not substantially augment peripheral T cell senescence beyond chronological aging but is characterized by a distinct immune signature featuring enhanced TNF-producing CD8+ effector responses and elevated TNF-related SASP factors. The parallel increases in TNFR1, TNF-producing CD8+ T cells, and frailty scores suggest a TNF-driven mechanism contributing to immune frailty, offering a potential target for inflammation-modulating interventions in aging. Funding Source Ministry of Science and ICT (MSIT), Republic of Korea Topic Categories Translational and Interventional Immunology (TI)

Elevated IgE Is Associated With Atrial Fibrillation and Promotes Cardiac Sympathetic Remodeling: A Translational Study 2309361

Abstract Introduction Mast cells reside in cardiac tissue and release inflammatory mediators upon IgE-mediated activation. While mast cells have been implicated in cardiac remodeling, the relationship between IgE and arrhythmias remains unexplored. We hypothesized that elevated IgE is associated with increased atrial fibrillation (AF) risk and that IgE-dependent mast cell activation promotes cardiac inflammation and sympathetic remodeling. Methods We performed a propensity-matched cohort study using TriNetX comparing patients with elevated IgE (>1000 IU/mL) versus normal IgE (< 100 IU/mL), matched on 29 covariates. The primary outcome was incident AF/flutter over 5 years. In parallel, C57BL/6J mice were sensitized to peanut allergen and fed peanut for 4 weeks. Hearts were analyzed for mast cell density, inflammatory cytokines, tyrosine hydroxylase (TH) as a sympathetic nerve marker, and sinoatrial node (SAN) macrophage infiltration. Results After matching, 54,007 patients per cohort were analyzed (mean age 29). Elevated IgE was associated with increased AF risk (1.54% vs 1.25%; OR 1.24, 95% CI 1.12-1.37, p < 0.0001). In mice, sensitization increased cardiac mast cells 3-fold (p < 0.01), an effect absent in IgE-deficient mice. Notably, much of the increase in mast cells was observed in or near cardiac ganglia and conducting system, key locations in the development or arrhythmia. Sensitized mice demonstrated elevated cardiac IL-1α, IL-6, IL-13, and TNFα. TH staining revealed 7-fold increased right atrial sympathetic nerve density (1.5% vs 0.2% area, p < 0.001). CD68 immunostaining showed increased macrophage infiltration within the SAN of sensitized animals. Conclusion Elevated IgE is associated with increased AF risk in young adults. IgE-dependent mast cell activation drives cardiac inflammation, sympathetic hyperinnervation, and SAN inflammation. These findings identify allergic sensitization as a novel arrhythmia risk factor with therapeutic implications. Funding Source n/a Topic Categories Neuroimmunology (NEUR)

Pilot study of gestational PFAS exposure on child blood transcriptional profiles 2259999

Abstract Introduction Per and polyfluoroalkyl substances (PFAS) are persistent fluorinated pollutants that have been shown to impair the immune response. We aimed to ascertain the association of prenatal PFAS exposure with childhood immune system status in those born either inside or outside a community with significant PFAS contamination in drinking water. Methods This pilot study used blood samples collected 10-15 years after birth from 24 mother-child pairs: 12 born inside the community (11 male/1 female) and 12 born outside (5 male/7 female). Blood PFAS levels were measured in samples from both mother and child. Transcriptome sequencing analysis of total RNAs isolated from child blood samples was performed to assess potential prenatal PFAS exposure-related gene expression changes. The differential gene expression analysis focused on 16 males (since there was only 1 non-community born female), and used birth community status as the surrogate for prenatal exposure. Covariates in the model included child BMI, years child spent in the community post-birth, ethnicity, and mom and child blood PFAS levels. Gene Ontology (GO) and Gene Set Enrichment Analyses (GSEA) were used to identify biological functions enriched in differentially expressed genes. Results We identified 842 differentially expressed genes between community-born/non-community born males. The top enriched GO pathways were involved in metabolism, protein breakdown, and cell cycle regulation. GSEA analysis using immune gene sets as reference revealed that the immune genes repressed in community-born males were previously associated with the response to RSV infection in infants. Conclusion Despite the small sample size, we were able to observe significant associations of prenatal PFAS exposure and changes in child blood gene expressions. Ongoing analysis includes cell type deconvolution analysis using RNA-seq data to investigate potential changes in immune cell types between birth communities. Funding Source CHHE ES025128, NIEHS R21ES029353, P42 ES031009, U24 ES037001 Topic Categories Computational and Systems Immunology (COMP)

Prevalence of IL12B rs3212227 Polymorphism in Patients With Plaque Psoriasis From Guatemala 2310585

Abstract Introduction Psoriasis is an immune-mediated and inflammatory disease in which the IL-12/IL-23 axis plays a key role. The IL12B gene encodes the p40 subunit shared by both cytokines and has been implicated in the differentiation of Th1 and Th17. The single nucleotide polymorphism rs3212227 in IL12B has been associated with psoriasis and psoriatic arthritis in Caucasian populations, with inconsistent findings in Hispanic populations. No prior studies have described the prevalence of this polymorphism in Guatemalan patients with psoriasis. Methods An observational and descriptive study was conducted in adult patients with plaque psoriasis attending a tertiary referral center in Guatemala. Clinical data were collected, including disease severity assessed by PASI and evaluation for psoriatic arthritis using CASPAR criteria. Genomic DNA was extracted from peripheral blood samples. The rs3212227 polymorphism was identified using polymerase chain reaction followed by Sanger sequencing. Descriptive statistics were used to summarize clinical characteristics and genotype and allele frequencies. Exploratory analyses were performed to assess relationships between genotype and clinical variables. Results Thirty-five patients were enrolled, of whom nine yielded sequencing of sufficient quality for genotyping. Genotype frequencies were 88.9% for TT and 11.1% for GG, with a G allele frequency of 11.1%. The mean PASI score was 13.3 ± 8.4. Twelve patients met criteria for psoriatic arthritis. No statistically significant associations were observed between the rs3212227 genotype and clinical variables. Conclusion In this cohort of Guatemalan patients with plaque psoriasis, the IL12B rs3212227 polymorphism was infrequent. Although limited sequencing yield restricted genotype-phenotype analysis, the detection of the G allele confirms its presence in the Guatemalan population and supports the need for larger studies to further characterize IL12B polymorphism in psoriasis within Central America. Funding Source Universidad Francisco Marroquín (partial institutional support for molecular biology consumables) Topic Categories Immune Mechanisms of Human Disease (HUM)

Fatigue‐Resistant Ferroelectric Hafnium Oxides by Modulating Grain Boundaries

ABSTRACT Recently, high‐endurance ferroelectric HfO 2 is highly desirable since the emerging of in‐memory computing requires non‐volatile memories not only to store data but also to execute computation, challenging writing/erasure switching reliability. Understanding and exploitation of the polarization fatigue diagram are crucial for improving endurance performances. Here, we show fatigue‐resistant Sm:HfO 2 thin films by modulating grain boundaries (GBs) in orientation‐controllable orthorhombic phase. On GBs, orientation discontinuity raises energy levels of O 2 p orbitals due to lattice distortion, which promote electron accumulation and yield a high‐symmetry structural transform at the boundary, facilitating 90° switching of out‐of‐plane domains because of lowered switching barrier. Then the domains are frozen in plane by the charged GBs and polarization fatigue takes place. By eliminating GBs associated with phase transform, remarkably‐improved fatigue resistance is achieved in uniform 180° switching, which exhibits the increase of fatigue‐free endurance by 200 times to 2.0 × 10 9 cycles with, more importantly, a large field‐cycling non‐volatile polarization of ∼60 µC/cm 2 , showing the state‐of‐the‐art endurance performances in hafnium oxides. Roadmaps of the fatigue scenarios are given based on key roles of GBs in domain configurations and switching pathways. Our findings open a new perspective for fatigue studying and guide the material design of high‐reliability hafnium oxide memories.

Reply to: “Liberalized Diets During Neutropenia: Ongoing Uncertainty in Hematopoietic Stem-Cell Transplantation” and “Impact of Transplant Type on Infection Risk in Studies of Neutropenic Diets”

Localized polarization-guided alignment control in carbon nanotube films via femtosecond-pulse optical post-processing

Abstract The physical properties of single-walled carbon nanotubes (CNTs) are highly sensitive to their alignment; therefore, making precise alignment control a central requirement for high-performance device architectures. However, conventional alignment techniques offer limited spatial programmability and remain inadequate for integrating heterogeneous CNT structures within a single film. Here, we report an optical post-processing technique to locally control the alignment of CNTs. We demonstrate that femtosecond-pulsed laser processing enables polarisation-guided alignment control of CNTs after film formation (post-processing). This process produces sub-micrometre scale locally aligned CNTs with thickness exceeding 200 nm and a nematic order parameter of 0.93 (strong directional order), demonstrating a high degree of orientational order and addressing a key bottleneck in spatially heterogeneous CNT integration. Additionally, these laser-aligned CNTs exhibit a direction-dependent optical and electrical response, functioning as a terahertz polariser with a polarisation ratio of 24.7; therefore, this technique enables the applications of CNT devices integrating heterogeneous structures like division-of-focal-plane polarisation cameras and on-chip polarisation routing.

Innovative MESF Standards for Accurate Quantification of Biological Nanoparticles in Flow Cytometry 2306500

Abstract Introduction The quantification of fluorescence intensity in flow cytometry is important for instrument sensitivity characterization and standardization of results. One of the key tools in this regard is Molecules of Equivalent Soluble Fluorochrome (MESF) beads. These beads are essential for standardizing fluorescence measurements and ensuring consistency across different experiments and instruments. Methods The quantification of fluorescence intensity in flow cytometry is important for instrument sensitivity characterization and standardization of results. One of the key tools in this regard is Molecules of Equivalent Soluble Fluorochrome (MESF) beads. These beads are essential for standardizing fluorescence measurements and ensuring consistency across different experiments and instruments. Results Preliminary evaluation using the CytoFLEX nano Flow Cytometer has confirmed the potential utility of the new nano-sized MESF beads Conclusion Once fully developed, these beads are anticipated to become an essential tool for MESF characterization and for standardizing instruments and assays in the growing field of small particle flow cytometry Funding Source n/a Topic Categories Technological Innovations in Immunology (TECH)

Tissue-specific regulation of human secondary lymphoid organ responses: a systems approach 2307169

Abstract Introduction Naïve B and T cells are activated within secondary lymphoid organs (SLOs) — either lymph nodes (LNs) or the spleen. Depending on the metabolic and antigenic environment during activation, lymphocytes alter their differentiation trajectories to adapt to the tissue of activation (ie, a4b7 induction by retinoic acid signaling). Despite the knowledge that organs have vastly different microenvironments, we know relatively little about lymphocyte fates in SLOs draining distinct organs in humans. Methods We profiled major SLO immune cell subtypes in human PBMCs and matched spleen or pancreatic lymph nodes (pancLN) using a 39-plex CyTOF panel. Following our initial assay, we then screened T, B, stromal, and myeloid subsets from 6 SLO regions (spleen, tonsil, inguinal, mesenteric, lung, and pancreatic LN) and PBMCs for expression of a total of 345 protein antigens using cytometry by time of flight (CyTOF). Results We find a donor-consistent pattern of CD69+ CD4 and CD8+ T cells, across naïve, effector and memory subsets, preferentially present in pancLNs. These CD69+ T cells have differing proteomic characteristics from their CD69- counterparts, within the same subset. Additionally, through our high-content proteomic screen, we identify protein antigens preferentially expressed on otherwise identical phenotypic subsets in a tissue-specific manner. Conclusion T cell expression of CD69, a widespread phenomenon in pancLNs, may influence the development and response to pancreatic insults and thus warrants further characterization. More generally, while SLOs themselves are developmentally and functionally similar, we find tissue-driven induction of previously undiscovered activation profiles and cellular states that may modulate the immune response. Funding Source n/a Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)

TCR germline diversity reveals evidence of natural selection on variable and joining alpha chain genes 2250859

Abstract Introduction T cell receptors (TCRs) orchestrate T cell mediated immunity. While the somatic diversification of TCRs has been extensively studied, inherited genetic diversity in the TCR V, D, and J genes has remained poorly characterized due to the complex, repetitive nature of the TCR loci. As a result, the contribution of germline TCR variation to immune diversity and evolution has remained largely unexplored. Methods We analyzed long-read whole-genome sequencing from 2,668 globally diverse donors to resolve allelic diversity across TCR genes encoding the α, β, γ, and δ chains. Using a custom bioinformatics pipeline, discovered alleles for each gene from long-read genome assemblies and orthogonally confirmed they were expressed in human repertoires. Population-genetic analyses were applied to detect signatures of natural selection, and single-cell data was used to analyze functional phenotypes. Results We generated a near-complete map of human TCR germline diversity, capturing over 94% of common alleles. We discovered 530 novel V gene alleles, representing a 361% increase in the number of known alleles. Nearly every amino acid position within V genes exhibited polymorphism, including chemically divergent residues at antigen-contacting sites. We found pervasive evidence of pathogen-driven natural selection on TCR genes, including diversifying selection across CDR and framework codons, balancing selection on a TRAJ gene critical for anti-influenza responses, and positive selection on a TRAV gene. We find TCR allelic polymorphism alters core functional properties of T cells, including thymic fate commitment, phenotypes in diseased tissues, and cell-surface receptor abundance. Conclusion Collectively, our findings position inherited variation in TCR genes as a key axis of immunological diversity that shapes interindividual differences in immune responses. The allelic map we develop enables future studies that study the impact inherited TCR variation across diverse contexts. Funding Source NIH grants R01AR063759, P01AI148102, U01HG012009, R56HG013083, and T32GM144273. Topic Categories Computational and Systems Immunology (COMP)

Deciphering Translational Insights from Mouse Model to Human Tumors Using Imaging Mass Cytometry 2259293

Abstract Introduction Glioblastoma (GBM) is highly aggressive disease due to rapid growth, therapeutic resistance and recurrence. Its spatial heterogeneity creates distinct niches, including necrotic cores, vascular regions and immune-suppressed areas, complicating treatment. Mouse models are widely used in neuro research due to conserved brain architecture enabling tissue-wide spatial studies. However, translating insights to humans requires high-resolution, multiplexed spatial technologies with high data quality. Imaging Mass Cytometry™ (IMC™) technology allows quantitative spatial proteomic analysis without issues like autofluorescence or tissue damage. Methods In this study, the Hyperion™ XTi Imaging System was used with 40-plus-marker panels combining mouse and human immuno-oncology and neurophenotyping kits to analyze spatial biology in mouse and human GBM tissues, respectively. Data analysis with pixel clustering and single-cell quantification identified conserved spatial features across species, revealing a heterogeneous tumor microenvironment (TME). Results Conserved spatial features were detected in both human and mouse GBM samples, highlighting striking heterogeneity. Multiple GBM subregions were located in both mouse and human tissues containing replicating Olig-2+ cells. A high concentration of infiltrated immune cells was present in human and mouse GBM, although spatial distribution was distinct. Spatial segmentation quantitatively distinguished tumor subregions, including differentiated tumor cells, immune hot and cold zones, stromal compartments, angiogenic vasculature and extracellular matrix. Conclusion The study demonstrates the utility of IMC technology in bridging mouse-human translational research by enabling cross-species validation of TME markers. Access to this information facilitates accelerated discovery of biomarker and targets for cancer therapies. For Research Use Only. Not for use in diagnostic procedures. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

The Dichotomy of Tumor Control by Recruited and Resident Tumor-Associated Macrophages 2253531

Abstract Introduction Tumor-associated macrophages (TAMs) can either promote or suppress tumor progression depending on their phenotype and localization. TAMs include monocyte-derived recruited macrophages (recMacs) and tissue-resident interstitial macrophages (IMs), but the spatial and functional diversity of IMs within the tumor microenvironment (TME) remains unclear. Methods Single-cell and spatial transcriptomic analyses were used to define macrophage heterogeneity and chemokine expression in the lung TME. Flow cytometry and immunofluorescence characterized distinct IM subsets. DC based neoantigen vaccination combined with transient CCR5 inhibition (Maraviroc) applied to assess monocyte trafficking and antigen presentation. Results Two major IM subsets were identified: CD206hi IMs expressing Cxcl9, Cxcl10, and Cxcl13 promoted tertiary lymphoid structure (TLS) formation, lymphocyte recruitment, and anti-tumor immunity, whereas Ccl2-expressing IMs recruited pro-tumor recMacs expressing Spp1, Vegfa, Arg1, and Cd274 (PD-L1), sustaining an immunosuppressive niche. Spatial transcriptomics localized Cxcl13+ IMs to bronchovascular and pleural niches near TLS sites, whereas Ccl2+ IMs and recMacs dominated tumor cores. Bone marrow chimera experiments confirmed that IM-derived CCL2, not endothelial or monocyte sources, drives recMac recruitment and tumor progression. Functionally, recMacs acted as immunosuppressive antigen-presenting cells in draining lymph nodes. Short-term CCR5 blockade with Maraviroc during dendritic cell-based neoantigen vaccination inhibited monocyte trafficking and enhanced tumor control. Conclusion Lung IMs display distinct spatial and functional roles in shaping the TME. Chemokine-producing CD206hi IMs sustain anti-tumor immunity, while CCL2-producing IMs and recMacs promote tumor growth. Targeting the CCL2—CCR2/CCR5 axis while preserving chemokine-producing IMs offers a promising strategy to augment cancer immunotherapy and neoantigen vaccine efficacy. Funding Source National Institutes of Health (NIH) grants: NIH grants R35 HL155458 (C.V.J.) National Cancer Institute Cancer Center Support Grant 5P30CA023108 (F.W.K.) NIH NIGMS P20GM130454 (F.W.K.) NIH S10 1S10OD030242 (F.W.K.) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

The impact of sensory neurons on tumor burden and immune response in NSCLC 2260151

Abstract Introduction Non-small cell lung cancer (NSCLC) is a malignancy of the epithelial cells in the lung originating from the central bronchi spreading to the terminal alveoli. It is the most common form, accounting for 85% of diagnoses. The low 5-year survival rate of 28% is due to acquired treatment resistance to standard of care anti PD-L1 immunotherapy. Therefore, it is pertinent to understand NSCLC immune signaling and fully describe cellular niches within the tumor microenvironment. Sensory neurons of the peripheral nervous system (PNS) have been shown to modulate immune responses across cancer types. Increased innervation and neuropeptide secretion is associated with increased tumor burden and dysregulated immune cell function. Neuropeptide substance P (SP) has been shown to drive breast cancer metastasis, and sensory neurons contribute to regulating immune responses in allergies, homeostasis, and infection. Methods In a tumor injectable mouse model of NSCLC with KRAS and p53 mutations (KP), lung tissue was broad cell immunophenotyped, and immunofluorescently stained with neuronal, immune, and tumoral markers. Cell supernatant was used for neuropeptide ELISA and cytokine analysis. This was performed in C57BL/6 and Tac1KO mice. Results SP immunofluorescence staining and ELISA showed increased expression in KP injected mice compared to control. When the SP-encoding gene Tac1 is knocked out, tumor burden is increased. We hypothesize this is due to dysregulated immune cell populations, particularly macrophages. Conclusion To approach NSCLC from a new perspective, we probe the impact of sensory neurons and neuropeptides on immune response and tumor burden in a KP tumor injectable mouse model, where we knockout neuropeptide SP. To better understand potential mechanism and neuron induced modulation of the tumor microenvironment, we plan to investigate neuropeptide level expression and immunophenotyping within the tumor injectable mouse model, human patient samples, and human co-culture in vitro models of NSCLC. Funding Source R01HL165259-01A, R01HL165259-03S2 Topic Categories Neuroimmunology (NEUR)

Spatial phenotyping and characterization of phosphorylated STATs in human and mouse inflammatory bowel disease tissues 2333539

Abstract Introduction Ulcerative colitis (UC) and Crohn’s disease (CD) are types of inflammatory bowel disease (IBD), a chronic inflammatory condition in which the gut epithelium is continually damaged and unable to fully repair itself. Many types of immune cells, including neutrophils, macrophages, and T cells, can contribute to this damage. Several signaling pathways have been implicated in IBD, including the JAK/STAT pathway, which can be aberrantly activated. STAT1 and STAT3 are key members of the pathway frequently activated in IBD. Activation of STAT1 drives inflammation, but activation of STAT3 can have pro- or anti-inflammatory effects depending on the cellular context. Methods Using normal, CD, and UC tissue samples from human and mouse colon, we performed a SignalStar® multiplex immunohistochemistry experiment to characterize active, or phosphorylated, STAT3 and STAT1 (p-STAT3, p-STAT1) as well as phenotyping markers to identify epithelial cells and subsets of immune cells: regulatory T cells, Th1 cells, neutrophils, and M1- and M2-like macrophages. Results We did not detect p-STAT1+ cells in human tissues but observed a dramatic increase in p-STAT1+ cells in mouse UC compared to normal colon. p-STAT3+ cells were present in both human and mouse tissues but displayed more subtle differences. Many p-STAT3+ cells were not labeled by the phenotyping readouts in the panel, but we did observe p-STAT3+FoxP3+ and p-STAT3+MPO+ cells in human CD and UC. In mouse UC, we detected p-STAT3+ cells positive for F4/80, CD86, and CD206. Phenotypic trends in human IBD included increased numbers of MPO+, CD3+, FoxP3+, and CD206+ cells, while the most striking change in mouse tissue was the increase in F4/80+ cells in UC. Conclusion Although we did not phenotype all p-STAT3+ cells, we were able to determine that the p-STAT3+ cells were primarily non-epithelial cells, including macrophages and neutrophils; STAT3 inhibition may represent a therapeutic approach for treating IBD. Funding Source N/A Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)

Directed Construction of Hierarchical Porous Carbon With Ultrahigh Surface Area for High‐Density Methane Storage at Room Temperature

ABSTRACT Efficient methane storage remains a fundamental challenge for the deployment of adsorbed natural gas technologies, owing to the long‐standing difficulty of simultaneously achieving high gravimetric and volumetric storage capacities. Here, we report a directed materials‐design strategy that links molecular precursor topology to defect evolution and hierarchical pore formation in porous carbons. By exploiting the distinct pyrolytic topologies of cyanide‐based ionic liquid anions, we program defect densities in carbon frameworks and guide the development of micro‐mesoporous architectures through chemical activation. This approach yields a hierarchical porous carbon with an ultrahigh Brunauer‐Emmett‐Teller area of 5011 m 2  g −1 and a physically accessible pore volume of 2.48 cm 3  g −1 as determined by skeletal density and tap density measurements, enabling exceptional methane storage performance at room temperature. At 298 K and 100 bar, this material achieves a gravimetric adsorption capacity of 0.48 g g −1 . Accordingly, its volumetric adsorption capacity reaches 228 cm 3 (Standard temperture and pressure, STP) cm −3 at a tap density of 0.337 g cm −3 and 275 cm 3 (STP) cm −3 at a compacted density of 0.407 g cm −3 . Beyond methane storage, our findings establish a generalizable paradigm for constructing high‐performance porous carbons by topologically programming defects and pore hierarchies, with implications for energy storage and gas adsorption technologies.

Multicenter Cohort Study of Original or Substitute Systemic Therapy With or Without Brain Radiotherapy for Extensive-Stage Small Cell Lung Cancer With Brain-Only Progression After First-Line Treatment

PURPOSE The optimal second-line strategy for patients with extensive-stage small cell lung cancer (ES-SCLC) developing brain-only progression (BOP) after first-line therapy remains undefined. We aimed to evaluate the efficacy of continuing the original systemic therapy versus switching strategies. METHODS This multicenter cohort study screened 889 patients with ES-SCLC. A total of 203 patients developing BOP were assigned to 3 second-line strategies: continuation of original systemic therapy plus brain radiotherapy (OTP + BRT), substitution therapy plus BRT (ST + BRT), or substitution therapy alone (ST). Inverse probability of treatment weighting was used to balance baseline characteristics. The primary end point was overall survival from second-line initiation (OS2). RESULTS In the inverse probability of treatment weighting–weighted analysis of 203 BOP patients, OTP + BRT demonstrated significantly superior median OS2 (14.7 months) compared with ST (10.2 months; hazard ratio [HR], 1.68; P = .028) and ST + BRT (9.8 months; HR, 1.67; P = .023). OTP + BRT also yielded improved median second-line progression-free survival (PFS) (8.0 months) versus ST (4.0 months; P = .024). Multivariable analysis confirmed OTP + BRT as an independent prognostic factor for improved survival. The benefit was most pronounced in patients with prior immunotherapy and longer initial PFS (≥7.5 months). No significant survival differences were observed among radiotherapy modalities (whole-brain radiotherapy v stereotactic radiosurgery). CONCLUSION For ES-SCLC patients with BOP, continuing the original systemic regimen plus BRT yields superior survival compared with switching systemic therapy. This supports a site-of-progression–directed strategy, effectively controlling the CNS sanctuary while maintaining an effective systemic backbone.

Distortion-engineered C1-symmetric inorganic molecular cages enable tunable chiroptical nonlinear optics with broad infrared transparency

Structural integrity of antigen receptors 2259926

Abstract Introduction Antibodies play a pivotal role in the adaptive immune system due to their ability to bind pathogens and toxins. There are two functionally similar, but structurally diverse antibodies that have arisen throughout evolution. Immunoglobulin (Ig)-based antibodies are found in jawed vertebrates, like humans; and variable lymphocyte receptors (VLRs), which are leucine rich repeats (LRRs)-based antibodies found in jawless vertebrates, like lampreys. While a broad baseline diversity is generated in both Ig-based and LRR-based antibodies, an additional form of antibody diversification—somatic hypermutation (SHM)--is unique to Ig-based antibodies. To date, there has been no solid evidence of SHM in lamprey LRR-based antibodies despite having genes that possess the enzymatic machinery to do so. This opens doors to evaluate possible differences in the negative structural impact somatic mutations would have on Ig- and LRR-based antibodies. Methods We will test this hypothesis by determining the SHM-like mutational tolerance of Ig-based and LRR-based antigen receptors in vitro, and defining diversity and maturation of Ig and VLR substrates in vivo. Results Preliminary computational data suggest that the diverse structures of Ig- and LRR-based antibodies vary in their capacity to maintain structural integrity during hypermutation, a process crucial for the expression of antibody diversity. Conclusion These results are consistent with a hypothesis that structural stability constraints may play a role in real-time protein mutability potential and that Ig-based antibodies are able to express greater real-time diversity than LRR-based antibodies. This will deliver biophysical insights into the aptitude of evolutionarily distinct but functionally convergent adaptive immune receptors for mutation-driven diversification. Funding Source National Science Foundation Graduate Research Fellowship Program (NSF GRFP) DGE 2140743, Ruth L. Kirschstein Predoctoral Individual National Research Service Award (NIH F31) 1F31AI186232, FujiFilm Fellowship Topic Categories Veterinary and Comparative Immunology (VET)

Identification of correlates of HIV-1 Neutralizing Antibodies through a systems serology approach 2307607

Abstract Introduction Antibodies utilize their antigen-binding fragment (Fab) and fragment crystallizable (Fc) domains to provide protection against infectious pathogens. Recent work has shown that the Fc region plays an as-yet fully understood role in antibody breadth coverage and neutralization potency. We sought to identify antibody features correlated to neutralization capacity at the systems level to HIV-1. Methods A systems-based predictive neutralizing antibody (SNAb) assay was used to quantify HIV-1 neutralization across diverse envelope glycoproteins representing multiple clades and subtypes, using specimens from HIV-vaccinated (Ad26/MVA) non-human primates (NHPs). These NHPs were further subdivided into groups receiving the monoclonal antibody (mAb) PGT121 or placebo to characterize how exogenous mAbs influence the neutralizing antibody profile. Results Predicted neutralizing antibodies to HIV-1 Env isolates and clades were quantified through SNAb, and showed heterogeneous neutralization capacities for all treatment arms. Correlations between antibody binding and Fc-receptor binding antibodies to the predicted neutralization titers are ongoing. Conclusion Our approach provides a method for dissecting correlates of HIV-1 neutralizing activity that may inform future vaccine and/or mAb therapy design. Future studies understanding how these neutralization signatures relate to latent reservoir expansion/contraction are ongoing. Funding Source National Institute of Health, UM1AI164566 Topic Categories Vaccines and Immunotherapy (VAC)

Loss of EOMES in T Cells Accelerates Tumor Burden and Mortality in Middle Aged Mice 2250481

Abstract Introduction Aging profoundly reshapes the immune system, leading to impaired pathogen defense, increased cancer incidence, and chronic inflammation that drives tissue dysfunction. Among immune cells, T lymphocytes undergo one of the most pronounced age-related shifts, losing naïve populations and accumulating cytokine-producing memory cells. EOMES is a transcription factor essential for effector and virtual memory CD8+ T-cell differentiation and cytotoxic activity. EOMES+ T cells accumulate with age and contribute to tissue inflammation through sustained production of IFN-γ and other inflammatory mediators. While these cells may exacerbate sterile inflammation, their role in maintaining tumor immunosurveillance during aging remains poorly defined. To determine how EOMES+ T cells contribute to age-related inflammation and tissue dysfunction, we generated T-cell—specific Eomes knockout mice (CD8a-Cre; Eomes fl/fl) and aged them alongside wild-type littermates. Methods Lifespan, organ pathology, and immune phenotypes were assessed by necropsy, histology, flow cytometry, and multiplex immunohistochemistry for CD3, CD20, and Iba1. Results Contrary to our hypothesis that EOMES deletion would preserve a youthful T-cell profile, by 15 months of age 50% of Eomes-deficient mice had died compared with ∼15% of controls, and by 18 months survival was ∼25% versus ∼65%, respectively (P < 0.0001). Knockout mice also developed multifocal neoplasms absent in controls. Immunopathology revealed admixed Iba1+ macrophages and CD20+ B cells with minimal CD3+ T-cell neoplasia, consistent with histiocyte-rich B-cell lymphoma. Conclusion These findings demonstrate that loss of EOMES-dependent cytotoxic surveillance permits malignant transformation. We propose that although EOMES-dependent immunosurveillance is critical for tumor suppression, its persistent activation with age may also contribute to age-related chronic inflammation, possibly linking antitumor immunity to inflammaging. Funding Source NIH R01AG086447, AHA 940023 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)