Alteration of mechanical stresses in the murine brain by age and hemorrhagic stroke.

Residual mechanical stresses, also known as solid stresses, emerge during rapid differential growth or remodeling of tissues, as observed in morphogenesis and tumor growth. While residual stresses typically dissipate in most healthy adult organs, as the growth rate decreases, high residual stresses have been reported in mature, healthy brains. However, the origins and consequences of residual mechanical stresses in the brain across health, aging, and disease remain poorly understood. Here, we utilized and validated a previously developed method to map residual mechanical stresses in the brains of mice across three age groups: 5-7 days, 8-12 weeks, and 22 months. We found that residual solid stress rapidly increases from 5-7 days to 8-12 weeks and remains high in mature 22 months mice brains. Three-dimensional mapping revealed unevenly distributed residual stresses from the anterior to posterior coronal brain sections. Since the brain is rich in negatively charged hyaluronic acid, we evaluated the contribution of charged extracellular matrix (ECM) constituents in maintaining solid stress levels. We found that lower ionic strength leads to elevated solid stresses, consistent with its unshielding effect and the subsequent expansion of charged ECM components. Lastly, we demonstrated that hemorrhagic stroke, accompanied by loss of cellular density, resulted in decreased residual stress in the murine brain. Our findings contribute to a better understanding of spatiotemporal alterations of residual solid stresses in healthy and diseased brains, a crucial step toward uncovering the biological and immunological consequences of this understudied mechanical phenotype in the brain.

CD300e: Emerging role and mechanism as an immune-activating receptor.

As a transmembrane protein, CD300e is primarily expressed in myeloid cells. It belongs to the CD300 glycoprotein family, functioning as an immune-activating receptor. Dysfunction of CD300e has been suggested in many diseases, such as infections, immune disorders, obesity, and diabetes, signifying its potential as a key biomarker for disease diagnosis and treatment. This review is aimed to explore the roles and potential mechanisms of CD300e in regulating oxidative stress, immune cell activation, tissue damage and repair, and lipid metabolism, shedding light on its role as a diagnostic marker or a therapeutic target, particularly for infections and autoimmune disorders.

Emergence of nanoscale viscoelasticity from single cancer cells to established tumors.

Tumors are complex materials whose physical properties dictate growth and treatment outcomes. Recent evidence suggests time-dependent physical properties, such as viscoelasticity, are crucial, distinct mechanical regulators of cancer progression and malignancy, yet the genesis and consequences of tumor viscoelasticity are poorly understood. Here, using Wide-bandwidth AFM-based ViscoElastic Spectroscopy (WAVES) coupled with mathematical modeling, we probe the origins of tumor viscoelasticity. From single carcinoma cells to increasingly sized carcinoma spheroids to established tumors, we describe a stepwise evolution of dynamic mechanical properties that create a nanorheological signature of established tumors: increased stiffness, decreased rate-dependent stiffening, and reduced energy dissipation. We dissect this evolution of viscoelasticity by scale, and show established tumors use fluid-solid interactions as the dominant mechanism of mechanical energy dissipation as opposed to fluid-independent intrinsic viscoelasticity. Additionally, we demonstrate the energy dissipation mechanism in spheroids and established tumors is negatively correlated with the cellular density, and this relationship strongly depends on an intact actin cytoskeleton. These findings define an emergent and targetable signature of the physical tumor microenvironment, with potential for deeper understanding of tumor pathophysiology and treatment strategies.

Multiscale elasticity mapping of biological samples in 3D at optical resolution.

The mechanical properties of biological tissues have emerged as an integral determinant of tissue function in health and disease. Nonetheless, characterizing the elasticity of biological samples in 3D and at high resolution remains challenging. Here, we present a µElastography platform: a scalable elastography system that maps the elastic properties of tissues from cellular to organ scales. The platform leverages the use of a biocompatible, thermo-responsive hydrogel to deliver compressive stress to a biological sample and track its resulting deformation. By surrounding the specimen with a reference hydrogel of known Young's modulus, we are able to map the absolute values of elastic properties in biological samples. We validate the experimental and computational components of the platform using a hydrogel phantom and verify the system's ability to detect internal mechanical heterogeneities. We then apply the platform to map the elasticity of multicellular spheroids and the murine lymph node. With these applications, we demonstrate the platform's ability to map tissue elasticity at internal planes of interest, as well as capture mechanical heterogeneities neglected by most macroscale characterization techniques. The µElastography platform, designed to be implementable in any biology lab with access to 3D microscopy (e.g., confocal, multiphoton, or optical coherence microscopy), will provide the capability to characterize the mechanical properties of biological samples to labs across the large community of biological sciences by eliminating the need of specialized instruments such as atomic force microscopy. STATEMENT OF SIGNIFICANCE: Understanding the elasticity of biological tissues is of great importance, but characterizing these properties typically requires highly specialized equipment. Utilizing stimulus-responsive hydrogels, we present a scalable, hydrogel-based elastography method that uses readily available reagents and imaging modalities to generate resolved maps of internal elasticity within biomaterials and biological samples at optical resolution. This new approach is capable of detecting internal stiffness heterogeneities within the 3D bulk of samples and is highly scalable across both imaging modalities and biological length scales. Thus, it will have significant impact on the measurement capabilities of labs studying engineered biomaterials, mechanobiology, disease progression, and tissue engineering and development.

The longitudinal association between asthma severity and physical fitness by neighborhood factors among New York City public school youth.

PURPOSE: This paper aims to examine the association between asthma severity and one-year lagged fitness in New York City Public school youth by neighborhood opportunity. METHODS: Using the Child Opportunity Index 2.0 and individual-level repeated measures NYC Office of School Health (OSH) fitness surveillance data (2010-2018), we ran multilevel mixed models stratified by neighborhood opportunity, adjusting for sex, race/ethnicity, grade level, poverty status, and time. Asthma severity was based on a physician-completed Asthma Medication Administration Form (MAF) from each school year and drawn from the Automated Student Health Record (ASHR). RESULTS: Across all youth in grades 4-12 (n = 939,598; 51.7 % male; 29.9 % non-Hispanic Black, 39.3 % Hispanic; 70.0 % high poverty), lower neighborhood opportunity was associated with lower subsequent fitness. Youth with severe asthma and very low and low neighborhood opportunity had the lowest 1-year lagged fitness z-scores - 0.24 (95 % CI, -0.34 to -0.14) and - 0.26 (95 % CI, -0.32 to -0.20), respectively, relative to youth with no asthma and very high opportunity. CONCLUSIONS: An inverse longitudinal relationship between asthma severity and subsequent fitness was observed. Study findings have implications for public health practitioners to promote physical activity and improved health equity for youth with asthma, taking neighborhood factors into account.

SaLT&PepPr is an interface-predicting language model for designing peptide-guided protein degraders.

Protein-protein interactions (PPIs) are critical for biological processes and predicting the sites of these interactions is useful for both computational and experimental applications. We present a Structure-agnostic Language Transformer and Peptide Prioritization (SaLT&PepPr) pipeline to predict interaction interfaces from a protein sequence alone for the subsequent generation of peptidic binding motifs. Our model fine-tunes the ESM-2 protein language model (pLM) with a per-position prediction task to identify PPI sites using data from the PDB, and prioritizes motifs which are most likely to be involved within inter-chain binding. By only using amino acid sequence as input, our model is competitive with structural homology-based methods, but exhibits reduced performance compared with deep learning models that input both structural and sequence features. Inspired by our previous results using co-crystals to engineer target-binding "guide" peptides, we curate PPI databases to identify partners for subsequent peptide derivation. Fusing guide peptides to an E3 ubiquitin ligase domain, we demonstrate degradation of endogenous ß-catenin, 4E-BP2, and TRIM8, and highlight the nanomolar binding affinity, low off-targeting propensity, and function-altering capability of our best-performing degraders in cancer cells. In total, our study suggests that prioritizing binders from natural interactions via pLMs can enable programmable protein targeting and modulation.

Crystal ribcage: a platform for probing real-time lung function at cellular resolution.

Understanding the dynamic pathogenesis and treatment response in pulmonary diseases requires probing the lung at cellular resolution in real time. Despite advances in intravital imaging, optical imaging of the lung during active respiration and circulation has remained challenging. Here, we introduce the crystal ribcage: a transparent ribcage that allows multiscale optical imaging of the functioning lung from whole-organ to single-cell level. It enables the modulation of lung biophysics and immunity through intravascular, intrapulmonary, intraparenchymal and optogenetic interventions, and it preserves the three-dimensional architecture, air-liquid interface, cellular diversity and respiratory-circulatory functions of the lung. Utilizing these capabilities on murine models of pulmonary pathologies we probed remodeling of respiratory-circulatory functions at the single-alveolus and capillary levels during disease progression. The crystal ribcage and its broad applications presented here will facilitate further studies of nearly any pulmonary disease as well as lead to the identification of new targets for treatment strategies.

Intravital measurements of solid stresses in tumours reveal length-scale and microenvironmentally dependent force transmission.

In cancer, solid stresses impede the delivery of therapeutics to tumours and the trafficking and tumour infiltration of immune cells. Understanding such consequences and the origin of solid stresses requires their probing in vivo at the cellular scale. Here we report a method for performing volumetric and longitudinal measurements of solid stresses in vivo, and findings from its applicability to tumours. We used multimodal intravital microscopy of fluorescently labelled polyacrylamide beads injected in breast tumours in mice as well as mathematical modelling to compare solid stresses at the single-cell and tissue scales, in primary and metastatic tumours, in vitro and in mice, and in live mice and post-mortem tissue. We found that solid-stress transmission is scale dependent, with tumour cells experiencing lower stresses than their embedding tissue, and that tumour cells in lung metastases experience substantially higher solid stresses than those in the primary tumours. The dependence of solid stresses on length scale and the microenvironment may inform the development of therapeutics that sensitize cancer cells to such mechanical forces.

The peritumor microenvironment: physics and immunity.

Cancer initiation and progression drastically alter the microenvironment at the interface between healthy and malignant tissue. This site, termed the peritumor, bears unique physical and immune attributes that together further promote tumor progression through interconnected mechanical signaling and immune activity. In this review, we describe the distinct physical features of the peritumoral microenvironment and link their relationship to immune responses. The peritumor is a region rich in biomarkers and therapeutic targets and thus is a key focus for future cancer research as well as clinical outlooks, particularly to understand and overcome novel mechanisms of immunotherapy resistance.

The longitudinal association between asthma severity and physical fitness among new York City public school youth.

Severe persistent childhood asthma is associated with low physical activity and may be associated with poor physical fitness. Research on the asthma severity-fitness association longitudinally and across sociodemographic subgroups is needed to inform fitness interventions targeting youth with asthma. We evaluated the relationship between asthma severity (categorized as severe, mild, or no asthma) and subsequent fitness in New York City (NYC) public school youth enrolled in grades 4-12 using the NYC Fitnessgram dataset (2010-2018). Longitudinal mixed models with random intercepts were fit to test the association between asthma severity and one-year lagged fitness z-scores by clustering repeated annual observations at the student level. Models were adjusted for sex, race/ethnicity, grade level, poverty status, time, and stratified by sociodemographic factors. The analytic sample included 663,137 students (51% male; 31% non-Hispanic Black, 40% Hispanic; 55% in grades 4-8, 70% high poverty; 87%, 11% and 1% with no, mild, and severe asthma, respectively). Students with severe asthma and mild asthma demonstrated -0.19 (95% CI, -0.20 to -0.17) and - 0.10 (95% CI, -0.11 to -0.10), respectively, lower fitness z-scores in the subsequent year relative to students without asthma. After stratifying by demographics, the magnitude of the asthma severity-fitness relationship was highest for non-Hispanic white vs. all other racial/ethnic subgroups, and was similar across sex, grade level, and household poverty status. Overall, we observed an inverse longitudinal relationship between asthma severity and subsequent fitness among urban youth, particularly non-Hispanic Whites. Future research should examine how neighborhood-level factors impact the asthma severity-fitness relationship across racial/ethnic subgroups.

Association of the urinary polycyclic aromatic hydrocarbons with sex hormones stratified by menopausal status older than 20 years: a mixture analysis.

We examined the relationships between exposure to polycyclic aromatic hydrocarbons (PAH) metabolites and sex hormones in pre- and postmenopausal women from the 2013-2016 National Health and Nutrition Examination Survey. The study comprised 648 premenopausal and 370 postmenopausal women (aged 20 years or older) with comprehensive data on PAH metabolites and sex steroid hormones. To evaluate the correlations between individual or mixture of the PAH metabolites and sex hormones stratified by menopausal status, we used linear regression and Bayesian kernel machine regression (BKMR). After controlling for confounders, 1-Hydroxynaphthalene (1-NAP) was inversely associated with total testosterone (TT), and 1-NAP, 3-Hydroxyfluorene (3-FLU), and 2-Hydroxyfluorene (2-FLU) were inversely associated with estradiol (E2). 3-FLU was positively associated with sex hormone-binding globulin (SHBG) and TT/E2, whereas 1-NAP and 2-FLU were inversely associated with free androgen index (FAI). In the BKMR analyses, chemical combination concentrations at or above the 55th percentile were inversely connected to E2, TT, and FAI values but positively correlated with SHBG when compared with the matching 50th percentile. In addition, we only found that mixed exposure to PAHs was positively associated with TT and SHBG in premenopausal women. Exposure to PAH metabolites, either alone or as a mixture, was negatively associated with E2, TT, FAI, and TT/E2 but positively associated with SHBG. These associations were stronger among postmenopausal women.

Correlation of Serum Chemokine (C-C Motif) Ligand 21 and Heat Shock Protein 90 with Preeclampsia.

Objective: The study aimed to explore the correlation of serum chemokine (C-C motif) ligand 21 (CCL21) and heat shock protein 90 (Hsp90) with preeclampsia (PE). Methods: Between June 2021 and June 2022, 50 pregnant women with PE were included in the PE group, and 50 healthy pregnant women were included in the control group. The serum levels of CCL21 and Hsp90 were compared between the two groups. Results: PE patients showed significantly higher levels of CCL21 and Hsp90 than healthy pregnant women (P < 0.05). Correlation analysis showed a positive correlation between CCL21 and Hsp90 levels (r > 0, (P < 0.05)). Binary logistic regression analysis suggested that high expression of CCL21 and Hsp90 were influencing factors for PE (OR >1, (P < 0.05)). The area under the receiver operating characteristic (AUC) curves of Hsp90 and CCL21 levels for predicting PE were 0.895 and 0.864, respectively, suggesting a good predictive value. Conclusion: Serum CCL21 and Hsp90 show great potential as disease markers for PE prediction. Further trials are, however, required prior to clinical promotion.

A Study of Heat Shock Protein 90 and Serum CCL21 Expression in Pregnant Women with Preeclampsia.

Objective: The purpose of the study was to determine the significance of heat shock protein 90 (HSP 90) and serum chemokine ligand 21 (CCL-21) in pregnant women with preeclampsia (PE). Methods: From June 2021 to June 2022, the study enrolled 100 women undergoing obstetric examinations and delivering in our hospital; 50 PE patients undergoing routine obstetric examinations and delivering during the same period were enrolled in the research group; according to the severity, they were divided into mild PE and severe PE groups, while 50 healthy pregnant women undergoing obstetric examinations and delivering in our hospital during the same period were enrolled in the control group. In a subsequent analysis, serum levels of CCL-21 and HSP90 were compared between the two groups, and the correlation among CCL-21, HSP 90, and PE severity was analyzed. Results: An overall total of 50 patients with PE were enrolled in the study, which included 32 patients with mild PE and 18 patients with severe PE. Patients with severe PE had lower mean arterial pressure (MAP), HSP 90, and CCL21 index levels than those with mild PE; MAP, HSP 90, and CCL21 in the severe PE group were higher than those in the mild PE group, but the difference was not statistically significant; In the research group, MAP was weakly correlated with HSP90 concentration and CCL21 concentration, with correlation coefficients of 0.33 and 0.30, respectively, and the correlation analysis was significant. Conclusion: Patients with PE showed significantly increased serum concentrations of HSP90 and CCL-21, but a significant difference did not exist between mild and severe PE. In addition, there was a weak relationship between HSP90 and CCL-21 concentrations in PE patients and MAP, suggesting that HSP90 and CCL-21 play an instrumental role in the pathogenesis of PE, although more studies are needed to clarify the exact mechanisms.

Growth and Gastrointestinal Tolerance in Healthy Term Infants Fed Milk-Based Infant Formula Supplemented with Five Human Milk Oligosaccharides (HMOs): A Randomized Multicenter Trial.

Background: Five of the most abundant human milk oligosaccharides (HMOs) in human milk are 2'-fucosyllactose (2'-FL), 3-fucosyllactose (3-FL), lacto-N-tetraose (LNT), 3'-sialyllactose (3'-SL) and 6'-sialyllactose (6'-SL). Methods: A randomized, double-blind, controlled parallel feeding trial evaluated growth in healthy term infants fed a control milk-based formula (CF; n = 129), experimental milk-based formula (EF; n = 130) containing five HMOs (5.75 g/L; 2'-FL, 3-FL, LNT, 3'-SL and 6'-SL) or human milk (HM; n = 104). Results: No significant differences (all p ≥ 0.337, protocol evaluable cohort) were observed among the three groups for weight gain per day from 14 to 119 days (D) of age, irrespective of COVID-19 or combined non-COVID-19 and COVID-19 periods. There were no differences (p ≥ 0.05) among the three groups for gains in weight and length from D14 to D119. Compared to the CF group, the EF group had more stools that were soft, frequent and yellow and were similar to the HM group. Serious and non-serious adverse events were not different among groups, but more CF-fed infants were seen by health care professionals for illness from study entry to D56 (p = 0.044) and D84 (p = 0.028) compared to EF-fed infants. Conclusions: The study demonstrated that the EF containing five HMOs supported normal growth, gastrointestinal (GI) tolerance and safe use in healthy term infants.

Rotational state specific dissociation dynamics of D2O via the C̃(010) state: The effect of bending vibrational excitation.

The rotational state resolved photodissociation dynamics of D2O via the C̃(010) state has been investigated by using the D-atom Rydberg tagging time-of-flight technique combined with a tunable vacuum ultraviolet light source. The D-atom action spectrum of the C̃(010) ← X̃(000) band and the corresponding time-of-flight (TOF) spectra of D-atom photoproducts formed following the excitation of D2O to individual rotational transition have been measured. By comparison with the action spectrum of the C̃(000) ← X̃(000) band, the bending vibrational constant of the C̃ state for D2O can be determined to be v2 = 1041.37 ± 0.71 cm-1. From the TOF spectra, the product kinetic energy spectra, the vibrational state distributions of OD products, and the state resolved anisotropy parameters have been determined. The experimental results indicate a dramatic variation in the OD product state distributions for different rotational excitations. This illuminates that there are two distinctive coupling channels from the C̃(010) state to the low-lying electronic states: the homogeneous electronic coupling to the Ã1B1 state, resulting in vibrationally hot OD(X) products, and the Coriolis-type coupling to the B̃1A1 state, producing vibrationally cold but rotationally hot OD(X) and OD(A) products. Furthermore, the three-body dissociation channel is confirmed, which is attributed to the C̃ → 1A2 or C̃ → à pathway. In comparison with the previous results of D2O photolysis via the C̃(000) state, it is found that the v2 vibration of the parent molecule enhances both the vibrational and rotational excitations of OD products.

Photodissociation dynamics of CO2 + hv → CO(X1Σ+) + O(1D2) via the 3P1Πu state.

The vacuum ultraviolet (VUV) photodissociation of CO2 is important to understand the primary photochemical processes of CO2 induced by solar VUV excitation in the Earth's atmosphere. Here, we report a detailed study of vibrational-state-specific photodissociation dynamics of the CO(X1Σ+) + O(1D2) channel via the 3P1Πu state by using the time-sliced velocity-mapped ion imaging apparatus combined with the single VUV photoionization detection scheme. By recording the sliced images of the O(1D2) photoproducts formed by VUV photoexcitation of CO2 to the individual vibrational structure of the 3P1Πu state, both the vibrational state distributions of the counterpart CO(X1Σ+) photoproducts and the vibrational-state-specific product anisotropy parameters (ß) are determined. The experimental results show that photodissociation of CO2 at 108.22, 107.50, 106.10, and 104.76 nm yields less anisotropic (ß > 0) and inverted distributed CO(X1Σ+, v) photoproducts. The possible dissociation mechanism for the CO(X1Σ+) + O(1D2) channel may involve the non-adiabatic transition of excited CO2* from the initially prepared state to the 31A' state with potential energy barriers. While at 108.82 and 107.35 nm, the vibrational distributions are found to have the population peaked at a low vibrational state, and the anisotropy parameters turn out to be negative. Such variation indicates the possibility of another non-adiabatic dissociation pathway that may involve Coriolis-type coupling to the low-lying dissociative state. These observations show sclear evidence of the influence of the initially vibrational excitations on the photodissociation dynamics of CO2 via the 3P1Πu state.

Low LINC01272 predicts poor prognosis of non-small cell lung cancer and its biological function in tumor cells by inhibiting miR-1303.

Non-small cell lung cancer (NSCLC) is a malignant tumor associated with poor prognosis. The clinical value of long non-coding RNAs (lncRNAs) in the pathomechanism of various types of human malignancy has attracted increasing attention. The present study aimed to investigate the expression of LINC01272 in NSCLC and to determine its prognostic value and biological role. Tumor and adjacent non-tumor tissues from 108 patients with NSCLC and NSCLC cell lines were used in this study. The expression levels of LINC01272 and microRNA (miR)-1303 in tissues of patients and NSCLC cell lines were evaluated by reverse transcription quantitative PCR. The relationship between LINC01272 and the overall survival of patients with NSCLC was analyzed by Kaplan-Meier survival curve and log-rank test. Cox regression analysis confirmed the prognostic value of LINC01272 in patients with NSCLC. Cell Counting Kit-8 assay was used to evaluate the proliferation of NSCLC cells. The migration and invasion of NSCLC cells were determined using Transwell assays. The interaction between LINC01272 and miR-1303 in NSCLC was confirmed by dual-luciferase reporter assay. LINC01272 downregulation in NSCLC tissues was associated with worse overall survival in patients based on bioinformatics analysis. Furthermore, LINC01272 expression, which was decreased in NSCLC tumor tissues and NSCLC cells, was considered as an independent prognostic biomarker in NSCLC. In addition, LINC01272 overexpression inhibited NSCLC cell proliferation, migration and invasion. miR-1303 expression, which was increased in tumor tissues, was sponged by LINC01272 and negatively correlated with LINC01272 expression. miR-1303 expression reversed the inhibitory effects of LINC01272 on NSCLC cell function. In summary, the findings from this study suggested that LINC01272 expression, which was decreased in NSCLC tumor tissues and NSCLC cells, may be used as an independent prognostic biomarker for patients with NSCLC and that its overexpression may suppress NSCLC cell proliferation, migration and invasion by inhibiting miR-1303.

Rotational and nuclear-spin level dependent photodissociation dynamics of H2S.

The detailed features of molecular photochemistry are key to understanding chemical processes enabled by non-adiabatic transitions between potential energy surfaces. But even in a small molecule like hydrogen sulphide (H2S), the influence of non-adiabatic transitions is not yet well understood. Here we report high resolution translational spectroscopy measurements of the H and S(1D) photoproducts formed following excitation of H2S to selected quantum levels of a Rydberg state with 1B1 electronic symmetry at wavelengths λ ~ 139.1 nm, revealing rich photofragmentation dynamics. Analysis reveals formation of SH(X), SH(A), S(3P) and H2 co-fragments, and in the diatomic products, inverted internal state population distributions. These nuclear dynamics are rationalised in terms of vibronic and rotational dependent predissociations, with relative probabilities depending on the parent quantum level. The study suggests likely formation routes for the S atoms attributed to solar photolysis of H2S in the coma of comets like C/1995 O1 and C/2014 Q2.

Strong isotope effect in the VUV photodissociation of HOD: A possible origin of D/H isotope heterogeneity in the solar nebula.

The deuterium versus hydrogen (D/H) isotopic ratios are important to understand the source of water on Earth and other terrestrial planets. However, the determinations of D/H ratios suggest a hydrogen isotopic diversity in the planetary objects of the solar system. Photochemistry has been suggested as one source of this isotope heterogeneity. Here, we have revealed the photodissociation features of the water isotopologue (HOD) at λ = 120.8 to 121.7 nm. The results show different quantum state populations of OH and OD fragments from HOD photodissociation, suggesting strong isotope effect. The branching ratios of H + OD and D + OH channels display large isotopic fractionation, with ratios of 0.70 ± 0.10 at 121.08 nm and 0.49 ± 0.10 at 121.6 nm. Because water is abundant in the solar nebula, photodissociation of HOD should be an alternative source of the D/H isotope heterogeneity. This isotope effect must be considered in the photochemical models.

Solid stress impairs lymphocyte infiltration into lymph-node metastases.

Strong and durable anticancer immune responses are associated with the generation of activated cancer-specific T cells in the draining lymph nodes. However, cancer cells can colonize lymph nodes and drive tumour progression. Here, we show that lymphocytes fail to penetrate metastatic lesions in lymph nodes. In tissue from patients with breast, colon, and head and neck cancers, as well as in mice with spontaneously developing breast-cancer lymph-node metastases, we found that lymphocyte exclusion from nodal lesions is associated with the presence of solid stress caused by lesion growth, that solid stress induces reductions in the number of functional high endothelial venules in the nodes, and that relieving solid stress in the mice increased the presence of lymphocytes in lymph-node lesions by about 15-fold. Solid-stress-mediated impairment of lymphocyte infiltration into lymph-node metastases suggests a therapeutic route for overcoming T-cell exclusion during immunotherapy.