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PubMed1994

Oxidant stress inhibits pH regulatory mechanisms in murine peritoneal macrophages.

BACKGROUND: Maintenance of cytoplasmic pH (pHi) close to the physiologic range is vital to normal cellular homeostasis. We have previously reported that a vacuolar-type H(+)-adenosine triphosphatase (V-ATPase) situated in the plasma membrane of macrophages and poised to extrude protons from the cytoplasmic to the extracellular space is an important pHi regulatory mechanism. Since the inflammatory microenvironment is frequently characterized by the influx of cells known to release reactive oxygen metabolites, we performed studies to examine the effect of oxidant stress on pHi regulation in peritoneal macrophages. Specifically, the effect of hydrogen peroxide on V-ATPase-mediated proton extrusion from acid-loaded macrophages was investigated. METHODS: Thioglycollate-elicited murine peritoneal macrophages were exposed to varying concentrations of hydrogen peroxide and examined for their ability to recover from an acid-load. pHi was studied by preloading cells with the pH-sensitive fluorescent dye, bis-carboxyethyl-carboxyfluorescein, and monitoring changes in fluorescence under various conditions using a fluorescence spectrometer. RESULTS: Hydrogen peroxide caused a time- and dose-dependent decrease in proton pump-mediated pHi recovery in peritoneal macrophages. This effect occurred without cytotoxicity and was a specific effect as evidenced by the ability of catalase to reverse the inhibition. Since hydrogen peroxide is known to deplete intracellular ATP, a substrate for V-ATPase activity, we hypothesized that ATP depletion may underlie the effect. These studies showed that hydrogen peroxide-mediated ATP depletion was both necessary and sufficient for the effect. Finally, depletion of intracellular glutathione in vivo by using diethyl maleate increased the sensitivity of V-ATPase activity to oxidant stress. CONCLUSIONS: Oxidant stress within the inflammatory milieu impairs macrophage pHi regulation. This effect is magnified by depletion of intracellular antioxidants, as occurs during sepsis. This represents another mechanism whereby oxidants may contribute to cellular dysfunction associated with inflammatory states.

Adenosine Triphosphate↗
PubMed2001

Human primary CD4 + T cells activated in the presence of IFN-alpha 2b express functional indoleamine 2,3-dioxygenase.

Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in the catabolism of tryptophan. By creating a local microenvironment in which levels of tryptophan are low, IDO-expressing antigen-presenting cells (APC) could regulate T cell activation. This may be relevant to control both viral and bacterial replication as well as neoplastic cell growth. Interferon-alpha (IFN-alpha) is an antiviral cytokine affecting cellular differentiation. In addition, it reduces proliferation of CD4(+) T cells by several molecular mechanisms. To dissect the molecular steps responsible for the INF-mediated antiproliferative activity, we sought to determine whether activated primary CD4(+) T cells in the presence of IFN-alpha would produce IDO. We demonstrate here that IDO mRNA is not present in resting CD4(+) T cells. Stimulation with anti-CD3 plus interleukin-2 (IL-2) induces expression of IDO mRNA (about 2000 copies/150,000 cells), as determined by semiquantitative RT-PCR. When cells were stimulated in the presence of IFN-alpha, expression of IDO mRNA was significantly increased (more than 12,000 copies/150,000 cells). Functional analysis of IDO activity paralleled the results obtained with RT-PCR, demonstrating increased production of active enzyme in CD4(+) T cells stimulated in the presence of IFN-alpha. Our results indicate that IFN-alpha modulates levels of IDO produced by activated CD4(+) T cells. This would likely affect bystander cells by modifying levels of tryptophan in the local microenvironment.

Base Sequence↗
PubMed2005

Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho-Rho kinase axis and tumor microenvironment.

We recently reported that proteinase-activated receptors type I (PAR-1) are coupled to both negative and positive invasion pathways in colonic and kidney cancer cells cultured on collagen type I gels. Here, we found that treatments with the cell-permeant analog 8-Br-cGMP and the soluble guanylate cyclase activator BAY41-2272, and Rho kinase (ROK) inhibition by Y27632 or a dominant negative form of ROK lead to PAR-1-mediated invasion through differential Rac1 and Cdc42 signaling. Hypoxia or the counteradhesive matricellular protein SPARC/BM-40 (SPARC: secreted protein acidic rich in cysteine) overexpressed during cancer progression also commutated PAR-1 to cellular invasion through the cGMP/protein kinase G (PKG) cascade, RhoA inactivation, and Rac1-dependent or -independent signaling. Cultured primary cancer cells isolated from peritoneal and pleural effusions from patients with colon cancer or other malignant tumors harbored PAR-1, as shown by RT-PCR and FACS analyses. These malignant effusions also contained high levels of activated thrombin and fibrin, and induced a proinvasive response in HCT8/S11 human colorectal cancer cells. Our data underline the essential role of the tumor microenvironment and of several commutators targeting cGMP/PKG signaling and the RhoA-ROK axis in the control of PAR-1 proinvasive activity and metastatic potential of cancer cells in distant organs and peritoneal or pleural cavities. We also add new insights into the mechanisms linking the coagulation mediators thrombin and PAR-1 in the context of blood coagulation disorders and venous thrombosis often observed in cancer patients, as described in 1865 by Armand Trousseau.

Aged↗
PubMed1999

Can cellular phototoxicity be accurately predicted on the basis of sensitizer photophysics?

The phototoxicity of three structurally related photosensitizers (PS), deuteroporphyrin IX (DP) and monobromo (Br-DP) and dibromo (Br2-DP) derivatives, was studied in murine L1210 leukemia cells. These compounds were chosen on the basis of heavy-atom-induced differences in triplet yield, phi T, and lifetime, tau T, and used as tools to test a model for phototoxicity based on photophysical parameters. All three porphyrins were found to localize preferentially in the plasma membrane of L1210 cells by confocal fluorescence microscopy. A poor correlation was observed between the measured photodynamic efficacies of these PS and a model using photophysical parameters determined by laser flash photolysis in homogeneous solution. However, an excellent correlation was obtained when the same parameters measured directly in the cells were used. The biological microenvironment of the porphyrins in cells induces significant changes in the photophysics of the PS. Reduction in fluorescence yield, phi F, and phi T observed for Br2-DP in cell suspensions arises from self association of the molecule due to increased hydrophobicity and high local concentrations. The photophysical model was also tested for its ability to handle variations in the oxygen dependence of cellular phototoxicity of these PS. The good correlation achieved between laser flash photolysis data determined in cells and the measured phototoxicity under air, 1.5% and 0.5% O2-saturated conditions, proves the intermediacy of singlet oxygen. This study gives further credence to the direct use of photophysical techniques to elucidate photochemical mechanisms in biological media while highlighting the potential pitfalls of using solution data to predict photosensitizing potential.

Animals↗
PubMed1993

The blood-brain barrier: cellular basis.

Perfusion experiments with horseradish peroxidase have established that the morphological substrate of the blood-brain barrier is represented by microvascular endothelial cells. They are characterized by complexly arranged tight junctions and a very low rate of transcytotic vesicular transport. They express transport enzymes, carrier systems and brain endothelial cell-specific molecules of unknown function not expressed by any other endothelial cell population. These blood-brain barrier properties are not intrinsic to these cells but are inducible by the surrounding brain tissue. Type I astrocytes injected into the anterior eye chamber of the rat or onto the chick chorioallantoic membrane are able to induce a host-derived angiogenesis and some blood-brain barrier properties in endothelial cells of non-neural origin. Recently we have shown that this cellular interaction is due to the secretion of a soluble astrocyte derived factor(s). Astrocytes are also implicated in the maintenance, functional regulation and the repair of the blood-brain barrier. Complex interactions between other constituents of the microenvironment surrounding the endothelial cells, such as the basement membrane, pericytes, nerve endings, microglial cells and the extracellular fluid, take place and are required for the proper functioning of the blood-brain barrier, which in addition is regionally different as reflected by endothelial cell heterogeneity.

Animals↗
PubMedDate not supplied

Characterization of human skin-derived CD1a-positive lymph cells.

The phenotype and function of CD1a+ lymph cells is of considerable interest. By means of microsurgical lymph cannulation human lymph derived from normal skin was sampled. Cells were isolated and processed for immunocytochemistry, electron microscopy, flow cytometry and functional assays. The majority of the cells, (62%), were T cells. The other cells comprised CD1a+ cells (7%), monocytes/macrophages (8%), and B cells (1%); the remainder were erythrocytes or uncharacterized cells. The CD1a+ cells reacted with antibodies against protein S-100, HLA-DR, the Lag antigen, CD4, CD11a, CD11b, CD18, CD25, CD40, CD54, CD80 and CD86. Interestingly, a small prolow portion the of CD1a+ cells (about 5%) reacted with an antibody to CD14. The CD1a+ cells did not react with an antibody against human follicular dendritic cells nor were they CD19-, CD23-, E-cadherin- or factor XIIIa-positive. Both allogenic and antigen-specific T cell proliferation stimulated by antigen-presenting lymph cells were strongly inhibited by adding anti-CD80 and anti-CD86 antibodies. By electron microscopy Birbeck granules were detected in only 22% of the CD1a+ lymph cells and these cells exhibited an extensive ruffling of the surface. These findings demonstrate that CD1a+ lymph cells, which do not express the dermal dendritic cell marker factor XIIIa, resemble dendritic cells formerly designated as 'veiled' as well as lymphoid dendritic cells, suggesting that after migration to the regional lymphoid organs, Langerhans cells form a more differentiated population of dendritic cells specialized in sensitizing T lymphocytes. Our results add further support to the view that resident Langerhans cells may be precursors of lymphoid dendritic cells acquiring the final phenotype in the microenvironment of the lymph node.

Adult↗
PubMed2003

HIF-1alpha is essential for myeloid cell-mediated inflammation.

Granulocytes and monocytes/macrophages of the myeloid lineage are the chief cellular agents of innate immunity. Here, we have examined the inflammatory response in mice with conditional knockouts of the hypoxia responsive transcription factor HIF-1alpha, its negative regulator VHL, and a known downstream target, VEGF. We find that activation of HIF-1alpha is essential for myeloid cell infiltration and activation in vivo through a mechanism independent of VEGF. Loss of VHL leads to a large increase in acute inflammatory responses. Our results show that HIF-1alpha is essential for the regulation of glycolytic capacity in myeloid cells: when HIF-1alpha is absent, the cellular ATP pool is drastically reduced. The metabolic defect results in profound impairment of myeloid cell aggregation, motility, invasiveness, and bacterial killing. This role for HIF-1alpha demonstrates its direct regulation of survival and function in the inflammatory microenvironment.

Adenosine Triphosphate↗
PubMed1998

Tissue architecture: the ultimate regulator of epithelial function?

The architecture of a tissue is defined by the nature and the integrity of its cellular and extracellular compartments, and is based on proper adhesive cell-cell and cell-extracellular matrix interactions. Cadherins and integrins are major adhesion-mediators that assemble epithelial cells together laterally and attach them basally to a subepithelial basement membrane, respectively. Because cell adhesion complexes are linked to the cytoskeleton and to the cellular signalling pathways, they represent checkpoints for regulation of cell shape and gene expression and thus are instructive for cell behaviour and function. This organization allows a reciprocal flow of mechanical and biochemical information between the cell and its microenvironment, and necessitates that cells actively maintain a state of homeostasis within a given tissue context. The loss of the ability of tumour cells to establish correct adhesive interactions with their microenvironment results in disruption of tissue architecture with often fatal consequences for the host organism. This review discusses the role of cell adhesion in the maintenance of tissue structure and analyses how tissue structure regulates epithelial function.

Animals↗
PubMed2006

Osteoblastic activation in the hematopoietic stem cell niche.

Hematopoietic stem cells (HSC) are rare primitive cells capable of reconstituting all blood cell lineages throughout the life of an individual. The microenvironment in which stem cells reside is essential for their survival, self-renewal, and differentiation. This microenvironment, or HSC niche, has been difficult to define in bone and bone marrow, but recent studies from our laboratory and others have shown that osteoblasts, the bone-forming cells, are an essential regulatory component of this complex cellular network. We established that parathyroid hormone (PTH), through activation of the PTH/PTHrP receptor (PTH1R) in osteoblastic cells, could alter the HSC niche resulting in HSC expansion in vivo and in vitro and improving dramatically the survival of mice receiving bone marrow transplants. These findings are of great clinical appeal, because they suggest that a strategy aimed at modifying supportive cells in a stem cell niche can expand HSC. While a number of molecules have been found to be important for hematopoietic/osteoblastic interactions, we have focused on the Jagged1/Notch signaling pathway, which was necessary for the PTH-dependent HSC expansion. Since the Jagged1/Notch signaling pathway has been implicated in the microenvironmental control of stem cell self-renewal in several organ systems, definition of Jagged1 modulation, which is currently poorly understood, should provide additional molecular targets for stem cell regulation and advance the understanding of stem cell-microenvironmental interactions.

Animals↗
PubMed1999

Acute laryngitis in the rat induced by Moraxella catarrhalis and Bordetella pertussis: number of neutrophils, dendritic cells, and T and B lymphocytes accumulating during infection in the laryngeal mucosa strongly differs in adjacent locations.

Infectious laryngotracheitis results in fulminant respiratory distress. During the disease, the subglottic mucosa is selectively infected and swollen, the reason for this preference being unknown. Therefore, in the present study the immunoreaction of the laryngeal mucosa was studied in the rat after inhalation of either heat-killed Moraxella catarrhalis (PVG rats) or application of viable Bordetella pertussis (BN rats). The number of neutrophils, macrophages, dendritic cells, and T and B lymphocytes was determined in the mucosa of the supraglottic, glottic, and subglottic area of the larynx as well as in the trachea. After application of the pathogens, the mucosa of the subglottic area was significantly more affected than the glottic mucosa. Already 1 h after application of M. catarrhalis, not only neutrophils but also dendritic cells and T and B lymphocytes were found both subepithelially and within the epithelium. They showed a similar kinetic progression, although at a different level. Two hours after application of M. catarrhalis, at the peak of inflammation, dendritic cells (173 +/- 10 cells/0.1 mm2) outnumbered neutrophils (54 +/- 9 cells/0.1 mm2), T lymphocytes (25 +/- 2 cells/0.1 mm2), and B lymphocytes (4.3 cells/0.1 mm2). The subglottic area (and the trachea) contained about three to five times more cells than the glottic area. In contrast, the number of local macrophages was lower in the subglottic area (24 +/- 5 cells/0.1 mm2) compared with that of the glottic area (38 +/- 6 cells/0.1 mm2), and did not change after application of both M. catarrhalis and B. pertussis. Thus, infectious laryngotracheitis in the rat closely resembles the clinical picture in children. In addition, the present results show a major difference in cellular influx in the mucosa of the glottic and subglottic area. This demonstrates that even in two closely adjacent locations, inflammatory responses of different magnitudes can occur, and it underlines the importance of regulatory mechanisms specific for the respective microenvironment.

Animals↗
PubMed2026

A conserved grain-associated immunosuppressive niche in Sudanese patients with mycetoma.

Mycetoma is a neglected tropical disease caused by various bacterial and fungal pathogens that has a significant health impact across a broad geographically defined "mycetoma belt" spanning South America, Africa and Asia. Histologically, mycetoma is characterised by invasive and destructive granuloma development in the skin, deep tissues and bone, leading to tissue destruction, deformities and high morbidity. The presence of macroscopic, highly compacted pathogen microcolonies, or "grains," is a key diagnostic feature, and the formation of grains supports pathogen persistence and disease chronicity. However, there is a paucity of information on immune responses in mycetoma patients and on the relative importance of phylogeny and/or grains in establishing the local immune landscape. Here, we used spatial proteomics to examine the distribution of 43 immune-related proteins in surgical biopsies from 11 patients with mycetoma of bacterial (actinomycetoma; Actinomadura pelletierii and Streptomyces somaliensis; n = 6) and fungal (eumycetoma; Madurella mycetomatis; n = 5) origin. Using mixed-effects modelling, an exploratory analysis across species and pathogen classes revealed few significant differences in immune marker expression. In contrast, and independently of pathogen class, the cellular infiltrate closest to grain boundaries had higher per-cell expression of CD66b+ neutrophils, ARG1, and VISTA. The preferential accumulation of CD66b+ARG1+VISTA+ cells at grain boundaries was confirmed by quantitative immunofluorescence analysis. Hence, the local tissue microenvironment surrounding the mycetoma grain represents a specialised immunosuppressive niche, with parallels to the tumour microenvironment. Trial Registration The study was prospectively registered on ClinicalTrials.gov NCT04401969.

Adult↗
PubMed1994

Antibody to silicone and native macromolecules in women with silicone breast implants.

Silicone implants have been associated with the development of multiple organ system abnormalities, including rheumatic disorders, nervous system, pulmonary dysfunction associated with autoantibodies and abnormalities of cellular immunity. In this regards a number of case reports and series of articles have been described. We hypothesized that an immune reaction to silicone breast implants would include the host reactivity against silicone and the macromolecules within the microenvironment of the implant, and these autoantibodies may react with other tissue antigens far from the site of the implant. To test this hypothesis 520 Symptomatic women with Silicone Implants which have developed Silicone related Immunological disorders and have typically complained of breast pain, Myalgia-Arthralgia, fatigue, or generalized pain, were examined by their physician. Blood samples were obtained and examined for the presence of Silicone antibodies, Myelin Basic Protein and human serum albumin antibodies. These samples were then compared to 520 matched controls without implants. At least at the level of two standard deviation silicone specific antibodies, IgG, IgA IgM, IgE and IgG+IgA+IgM antibodies were detected above the mean of normal controls. When these antibodies were classified based on the specialty of the examining physician, the % of patients with Silicone Antibodies were varied; general practice 51.6, Rheumatology 58.7, and Plastic Surgery 83.3, which may relate to the severeness of the disease. Being that a large % of patients demonstrated very high levels of Myelin Basic Protein Antibodies, possible cross reactive antibodies were sought. However, absorption of highly positive sera for Silicone Antibodies with MBP did not change the levels of Silicone Antibodies. On the other hand, Silicone-HSA was able to reduce the antibody values significantly. This reduction in antibody levels by Silicone is the best indication for the specificity of these antibodies. Moreover when data for silicone antibodies and MBP antibodies was analyzed in patients some with high and others with medium or low levels of silicone antibodies, MBP antibodies did not correspond to the silicone antibody levels. Similarly human serum albumin antibodies which was significantly higher in patients with silicone implants did not correlate with levels of silicone antibodies. These results indicate that immune reaction to silicone and different tissue antigens do occur and they are initiated through different mechanisms. And since predominant antibody class against silicone, MBP and HSA was IgM, clonal activation of IgM is possible which certainly warrants further investigation.

Adult↗
PubMed1986

[Effect of estrone on formation of the focus of heterotopic hematopoiesis].

The effect of estrone injections on the heterotopic bone marrow organ formation was studied in (C57Bl X CBA)F1 mice by bone marrow shaft transplantation under the kidney capsule. Estrone injections resulted in femur marrow fibrosis, the increase in the weight of femur and heterotopic organ ossicle, drastic reduction in heterotopic organ cellularity. Depression of hemopoiesis in ectopic organ cannot be attributed to mechanical displacement of hemopoietic cells because a newly formed bone cavity under the kidney capsule was not closed. Thus, estrone had a detrimental effect on the creation of microenvironment in the heterotopic organ.

Animals↗
PubMed1995

VLA-4-dependent adhesion in follicular non-Hodgkin's lymphomas.

The cellular contact between B cells and follicular dendritic cells (FDCs) in the germinal center is thought to play a key role in B-cell maturation and proliferation. The adhesion pathway through the very late antigen 4 (VLA-4) on the B cells and the vascular cell adhesion molecule 1 (VCAM-1) on the FDCs support this binding process. The neoplastic follicular centers in follicular non-Hodgkin's lymphomas (FNHLs) have similar structures and cellular components to those of normal germinal centers, but their interaction between B cells and FDCs may be functionally disturbed. In view of this we analyzed the interaction between VLA-4 and VCAM-1 molecules in the germinal center microenvironment, both in neoplastic and normal follicles. The structural characterization of FNHLs and reactive lymph nodes was studied with indirect immunohistochemical stainings using monoclonal antibodies against VLA-4, VCAM-1, and fibronectin, with special reference to the reaction pattern in the normal and neoplastic follicles. In the reactive follicular centers most B cells did not show a positive reaction for VLA-4, except for moderate reaction products in the B cells of the light zone. In FNHLs, on the other hand, most follicular center B cells were positive for VLA-4. The reaction patterns of VCAM-1 and fibronectin in both normal and neoplastic follicular centers were not basically different. To investigate the interaction of VLA-4 with VCAM-1 in both neoplastic and normal follicular centers, we performed a frozen-section binding assay, which found decreased binding between VLA-4 and VCAM-1 in FNHLs. The results of this study indicated that the microenvironment in neoplastic follicular centers is different from that in their normal counterparts, in terms of the characteristic distribution pattern of the VLA-4-positive B cells, and the functional deterioration of the VCAM-1 on FDCs.

Cell Adhesion↗
PubMed1997

[Immunological aspects of endometriosis].

The effect of adherence process on Fallopian tubes and ovaries in late stages endometriosis is clear, but it is more important to understand pathophysiologic mechanism of infertility in minimal, mild endometriosis. Although the etiology of endometriosis is unknown, components of the immune system may be involved and play a central role in the pathogenesis of the disease by immunologically altering the peritoneal microenvironment. Increased number and activity of leucocyte subpopulations in the peritoneal fluid result in cytotoxic effects that exert adverse influence on spermatozoa, oocyte, germ cell interaction, and early embryo development, while cytokine and growth factor secretion stimulates or promotes cellular proliferation of endometriotic tissue in an "immunological tolerance" environment. The immunological aspects of endometriosis, including autocrine or paracrine pathways of intercellular communication, are reviewed.

Adolescent↗
PubMed2026

Comprehensive analysis suggests CRIF1 is a potential target in breast cancer associated with prognosis and immune infiltration.

BACKGROUND: CRIF1 is a multifunctional factor that regulates cell biological processes such as the cell cycle, cell proliferation, and energy metabolism, and it is a new molecule that contributes to the poor prognosis of many malignancies. However, its involvement in breast cancer development is not fully known. MATERIALS AND METHODS: To investigate the relationship between CRIF1 expression, prognosis, and clinical characteristics using The Cancer Genome Atlas (TCGA-BRCA). The relationship between CRIF1 expression and the immunological microenvironment was investigated using CIBERSORT, ESTIMATE. Breast tissue and CRIF1 expression were validated by IHC. A tiny interfering plasmid was designed to transiently transfect breast cancer cell lines, and proliferation-related functional tests were carried out. The effect of sh CRIF1 on tumor formation was confirmed using a subcutaneous tumor experiment in naked mice. RESULTS: We discovered that CRIF1 was highly elevated in breast cancer tissues and associated with a poor prognosis. CRIF1 stimulates breast cancer cell proliferation, migration, and invasion. Knockdown decreased PI3K/AKT/mTOR signaling, which boosted autophagy activity. Immune infiltration research revealed that patients with high CRIF1 expression had higher CD8+ T cell expression but reduced macrophage M2 expression. CONCLUSION: Upregulation of CRIF1 in breast cancer cells enhances malignant behavior, which may be mediated by PI3K/AKT/mTOR signaling and is linked to cellular autophagy.

Humans↗
PubMed2025

MOADE: a multimodal autoencoder for dissociating bulk multi-omics data.

In single cell biology, the complexity of tissues may hinder lineage cell mapping or tumor microenvironment decomposition, requiring digital dissociation of bulk tissues. Many deconvolution methods focus on transcriptomic assay, not easily applicable to other omics due to ambiguous cell markers and reference-to-target difference. Here, we present MOADE, a multimodal autoencoder pipeline linking multi-dimensional features to jointly predict personalized multi-omic profiles and cellular compositions, using pseudo-bulk data constructed by internal non-transcriptomic reference and external scRNA-seq data. MOADE is evaluated through rigorous simulation experiments and real multi-omic data from multiple tissue types, outperforming nine deconvolution pipelines with superior generalizability and fidelity.

Humans↗
PubMed2025

Neoadjuvant Immunotherapy Promotes the Formation of Mature Tertiary Lymphoid Structures in a Remodeled Pancreatic Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. In this study, we report the generation of a spatial multiomic atlas of PDAC tumors and tumor-adjacent lymph nodes from patients treated with combination neoadjuvant immunotherapies. Using machine learning-enabled hematoxylin and eosin image classification models, imaging mass cytometry, and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within and adjacent to TLS spanning distinct spatial niches and pathologic responses. Unsupervised learning identified TLS-specific spatial gene expression signatures that are significantly associated with improved survival in patients with PDAC. We identified spatial features of pathologic immune responses, including intratumoral TLS-associated B-cell maturation colocalizing with IgG dissemination and extracellular matrix remodeling. Our findings offer insights into the cellular and molecular landscape of TLS in PDACs during immunotherapy treatment.

Humans↗