Search Results - EGA European Genome-Phenome Archive

Human Pancreatic Beta Cell lncRNAs Control Cell-Specific Regulatory Networks

Recent studies have uncovered thousands of long non-coding RNAs (lncRNAs) in human pancreatic β cells. β cell lncRNAs are often cell type specific and exhibit dynamic regulation during differentiation or upon changing glucose concentrations. Although these features hint at a role of lncRNAs in β cell gene regulation and diabetes, the function of β cell lncRNAs remains largely unknown. In this study, we investigated the function of β cell-specific lncRNAs and transcription factors using transcript knockdowns and co-expression network analysis. This revealed lncRNAs that function in concert with transcription factors to regulate β cell-specific transcriptional networks. We further demonstrate that the lncRNA PLUTO affects local 3D chromatin structure and transcription of PDX1, encoding a key β cell transcription factor, and that both PLUTO and PDX1 are downregulated in islets from donors with type 2 diabetes or impaired glucose tolerance. These results implicate lncRNAs in the regulation of β cell-specific transcription factor networks.

Study EGAS00001002865

Exome-sequencing identifies new oncogenes and tumor suppressor genes recurrently altered in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. High-resolution copy number analysis of 125 tumors of which 24 were subjected to whole-exome sequencing identified 135 homozygous deletions and 994 somatic gene mutations with predicted functional consequences. We identified new recurrent alterations in 4 genes (ARID1A, RPS6KA3, NFE2L2 and IRF2) not previously described in HCC. Functional analyses demonstrated tumor suppressor properties for IRF2 whose inactivation, exclusively found in hepatitis B virus related tumors, leads to impaired TP53 function. Alternatively, inactivation of proteins involved in chromatin remodeling was frequent and predominant in alcohol related tumors. Moreover, activation of the oxidative stress metabolism and inactivation of RPS6KA3 were new pathways associated with WNT/beta-catenin activation, thereby suggesting a cooperative effect in tumorigenesis. This study shows the dramatic somatic genetic diversity in HCC, it reveals interactions between oncogene and tumor suppressor gene mutations markedly related to specific risk factors.

Study EGAS00001000217

Targeted sequencing of head and neck squamous cell carcinomas

Overall survival remains very poor for patients diagnosed with head and neck squamous cell carcinoma (HNSCC). Identification of additional biomarkers and novel therapeutic strategies are important for improving patient outcome. Patient-derived xenografts (PDXs), generated by implanting fresh tumor tissue directly from patients into immune-deficient mice, recapitulate many of the features of their corresponding clinical cancers, including histopathological and molecular profiles. Using a large collection of PDX models of HNSCC we demonstrate that rapid engraftment into immune-compromised mice is highly prognostic, and show that genomic deregulation of the G1/S checkpoint pathway correlates with engraftment. Furthermore, CCND1 and CDKN2A genomic alterations are predictive of response to the CDK4/6 inhibitor abemaciclib. Overall, our study supports the pursuit of CDK4/6 inhibitors as a therapeutic strategy for a substantial proportion of HNSCC patients, and demonstrates the potential of using PDX models to identify novel targeted therapies for those patients who have the poorest outcomes.

Study EGAS00001002979

Heritable pulmonary arterial hypertension in a large Iberian family

Data from a study of a large Iberian family (n=65 subjects, 5 generations) affected by pulmonary arterial hypertension (PAH) and segregating with the BMPR2 missense mutation p.Arg491Gln (rs137852749, c.1472G>A). PAH is a rare disease characterized by an abnormal rise in mean pulmonary arterial pressure (> or equal to 25 mmHg at rest), which, in turn, leads to a progressive increase in pulmonary vascular resistance and ultimately to death, due to right ventricular failure. Heritable PAH has an overall prevalence below 1 case per million adults and is defined by either the presence of a known genetic defect linked to the disease or a positive family history. Heritable PAH is inherited as an autosomal dominant disease. However, not all BMPR2 mutation carriers develop the disease, highlighting the presence of reduced penetrance. In this family, there are 22 mutation carriers from which 8 were diagnosed with heritable PAH and the other 14 were healthy at the time of examination.

Study EGAS00001003123

Comparison of 3 protocols for deriving pancreatic progenitors from hPSC with RNA-seq and ATAC-seq

Several distinct differentiation protocols for deriving pancreatic progenitors (PP) from human pluripotent stem cells have been described but it remains to be shown how similar the PP are across protocols, and how well they resemble their in vivo counterparts. Here we evaluated three differentiation protocols; performed RNA and ATAC-seq on isolated PP derived with these, and compared them to fetal human pancreas populations. This enabled us to define a shared transcriptional and epigenomic signature of the PP, including several genes not previously implicated in pancreas development. Furthermore, we identified a significant and previously unappreciated cross-protocol variation of the PP through multi-omics analysis and demonstrate how such information can be applied to refine differentiation protocols for derivation of insulin-producing beta-like cells. Together, our study highlights the importance of a detailed characterization of defined cell populations derived from distinct differentiation protocols, and provides a valuable resource for exploring human pancreatic development.

Study EGAS00001003513

Uterine_Atlas_Endometriosis

Uterine Atlas Endometriosis Endometriosis is a chronic inflammatory disease driven by oestrogen, affecting around 10% of women of child-bearing again world-wide. It is described by the presence of endometrium-like tissue outside of the uterus (ectopic endometriosis tissue) and debilitating chronic pain. There is a lack of understanding of endometriosis pathogenesis, as well as cellular composition of both the eutopic endometrium and ectopic endometriosis tissue of endometriosis patients.There are therefore two main aims for this study. Using single cell genomics and spatial methods we aim to: I) characterise endometrial cellular census in women with and without endometriosis II) characterise cellular census of ectopic endometriosis tissue Furthermore, we aim to establish endometrial organoids and endometriosis organoids from the samples collected and characterise these using single cell genomics and spatial methods. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Study EGAS00001004725

Variation in the Glucose Transporter gene SLC2A2 is associated with glycaemic response to metformin

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C-allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (p=6.6x10-14) greater metformin induced HbA1c reduction in 10,577 participants of European ancestry. rs8192675 is the top cis-eQTL for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. In obese individuals C-allele homozygotes at rs8192675 had a 0.33% (3.6mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes.This is about half the effect seen with the addition of a DPP-4 inhibitor, and equates to a dose difference of 550mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

Study EGAS00001001875

Immune trajectory of response and adverse effect in immunotherapy-treated hepatocellular carcinoma

Whilst anti-PD1 immune checkpoint blockade (ICB) has revolutionised treatment for many cancers, its response rates in hepatocellular carcinoma (HCC) remain modest, coupled with common incidences of immune-related adverse events (irAEs). To identify biomarkers and decipher the mechanisms for response and irAEs, we performed multi-dimensional immunoprofiling on peripheral blood and tissue collected before and during anti-PD1 ICB treatment from HCC patients. Single-cell analyses enabled us to identify peripheral biomarkers, in particular, CD11c+ antigen-presenting cells with varying degrees of HLA-DR expression and CD8 effector memory (EM) T cells with CXCR3 tissue-homing capability that are associated with both response and irAEs. We also dissected the mechanisms behind how these immune subsets interface between response and toxicity, showing their intersecting yet diverging trajectories leading to these distinct clinical fates. This study offers new insights on the mechanisms and potentially novel strategies to enhance response and ameliorate irAEs in cancer immunotherapy.

Study EGAS00001004843

Engineering large chromosomal deletions by CRISPR-Cas9

Arm-level chromosomal deletions are a prevalent and defining feature of cancer. A high degree of tumor-type and subtype specific recurrencies suggest a selective oncogenic advantage. However, due to their large size it has been difficult to pinpoint the oncogenic drivers that confer this advantage. Suitable functional genomics approaches to study the oncogenic driving capacity of arm-level deletions are limited. Here we present an effective technique to engineer arm-level deletions by CRISPR-Cas9 and create isogenic cell line models. We simultaneously induce double-strand breaks (DSBs) at two ends of a chromosomal arm and select the cells that have lost the intermittent region. Using this technique, we induced arm-level deletions on chromosome 11q (65 MB) and chromosome 6q (53 MB) in neuroblastoma cell lines. Such isogenic models enable further research on the role of arm-level deletions in tumor development and growth, and their possible therapeutic potential.

Study EGAS00001005134

Single-cell landscapes of primary glioblastomas and matched organoids and cell lines reveal variable retention of inter- and intra-tumor heterogeneity

Glioblastomas (GBMs) are aggressive primary malignant brain tumors characterized by extensive levels of inter- and intra-tumor genetic and phenotypic heterogeneity. Patient-derived organoids (PDOs) have recently emerged as useful models to study such heterogeneity. Here, we present bulk exome as well as single-cell genome and transcriptome profiles of primary IDH wild type GBMs from ten patients, including two recurrent tumors, as well as PDOs and brain tumor-initiating cell (BTIC) lines derived from these patients. We find that PDOs are genetically similar to and variably retain gene expression characteristics of their parent tumors. At the phenotypic level, PDOs appear to exhibit similar levels of transcriptional heterogeneity as their parent tumors, whereas BTIC lines tend to be enriched for cells in a more uniform transcriptional state. The datasets introduced here will provide a valuable resource to help guide experiments using GBM-derived organoids, especially in the context of studying cellular heterogeneity.

Study EGAS00001005227

Longitudinal Single-Cell Profiling Reveals Molecular Heterogeneity and Tumor-Immune Evolution in Refractory Mantle Cell Lymphoma

The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood. We characterize the cellular and molecular heterogeneity within and across patients and delineate the dynamic evolution of tumor and immune cell compartments at single cell resolution in longitudinal specimens from ibrutinib-sensitive patients and non-responders. Temporal activation of multiple cancer hallmark pathways and acquisition of 17q are observed in a refractory MCL. Multi-platform validation is performed at genomic and cellular levels in PDX models and larger patient cohorts. We demonstrate that the molecular targeting of BIRC5/survivin, locates at 17q and upregulates in resistant MCL tumor cells, results in marked tumor inhibition in preclinical models. In addition, we discovere notable differences in the tumor microenvironment including progressive dampening of CD8+ T cells and aberrant cell-to-cell communication networks in refractory MCLs. This study reveales diverse and dynamic tumor and immune programs underlying therapy resistance in MCL.

Study EGAS00001005019

Genomic landscape and PD-1 blockade in Natural-killer/T cell lymphoma

Natural killer/T-cell lymphoma (NKTL) is an aggressive malignancy with a predilection for Asian, Mexican and South American populations. With the exception of Japan, it is the most common mature T-cell lymphoma in Asia. NKTL presents as extranodal disease and mostly affects the upper aerodigestive tract. Neoplastic cells are invariably infected by the Epstein-Barr virus (EBV) and characterized by a cytotoxic phenotype. The genetic landscape of NKTL has been recently unraveled by discoveries describing recurring mutations altering the JAK-STAT pathway, epigenetic modifiers, the DDX3X gene and genetic predisposition in the HLA-DPB1 gene.The genomic landscape of NKTL has been interrogated by whole-exome sequencing, targeted sequencing and single nucleotide polymorphism arrays, but has yet been studied with whole-genome sequencing (WGS). In this study, we will use a combination of WGS, targeted-capture sequencing (TCS) and RNA sequencing data to explore the genetic landscape and its relevance to immunotherapy in NKTL

Study EGAS00001003828

Molecular profiling of metastatic uveal melanoma

Metastatic uveal melanoma is less well understood than its primary counterpart, has a distinct biology compared to skin melanoma and lacks effective treatments. Here we genomically profile metastatic tumors and infiltrating lymphocytes. BAP1 alterations were overrepresented and occurred in 29/32 of cases. An outlier tumor had high mutational burden associated with UV-damage. CDKN2A deletions also occurred, which are rarely present in primaries. We profiled recurrent copy number alterations associated with metastasis and performed a focused knockdown screen on overexpressed targets. We investigated the role of BAP1 by reintroducing a functional allele into a deficient patient-derived cell line, revealing a broad shift towards a transcriptomic subtype associated with better prognosis. Tumor-infiltrating lymphocytes were in several cases tumor-reactive, but expression of the immune checkpoint receptors TIM-3, TIGIT and LAG3 was abundant. This study represents the largest whole-genome analysis of uveal melanoma to date and presents an updated view of the metastatic disease.

Study EGAS00001004296

Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140

SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn’s disease (CD), suggesting a role in inflammation. We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD68+ CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte differentiation into inflammatory macrophages and lipopolysaccharide (LPS)-induced inflammatory activation. SP140 preferentially occupies transcriptional start sites (TSS) in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduced SP140 binding and thereby expression of SP140-bound genes. GSK761 inhibited the spontaneous expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal-mucosa. This study identifies SP140 as a druggable epigenetic therapeutic target for CD.

Study EGAS00001004460

Whole-exome sequencing and microRNA profiling predicted relapse risk of stage I lung adenocarcinomas

Despite the advance in precision therapy, about 20% of stage I non-small cell lung cancer patients suffer a relapse after surgical resection. To develop molecular signatures for relapse prediction of stage I lung adenocarcinoma (LUAD), we conduct comprehensive analyses of multiplatform molecular profiling from 113 treatment-naïve stage I Taiwanese LUAD patients. We identify 16 nonsynonymous non-sporadic point mutations (NSPOPMs) harbored at EGFR, KRAS, TP53, CTNNB1 and 6 other genes, and find that the Non-EGFR NSPOPMs were associated with early relapse in a dose-dependent manner via variant allele fraction (VAF). We define a score, maxVAF, to aggregate the VAFs of these NSPOPMs by the maximum value. MicroRNA expression analysis shows a strong correlation between miR-31 and maxVAF. Combining maxVAF with miR-31 led to a powerful risk prediction for surgically resected stage I patients (hazard ratio = 8.65, P = 0.001). Our study opens up more options for precision management of stage I LUAD patients.

Study EGAS00001004461

Differential expression profile of gluten-specific T cells identified by single-cell RNA-seq

Gluten-specific CD4+ T cells drive the pathogenesis of celiac disease and circulating gluten-specific T cells can be identified by staining with HLA-DQ:gluten tetramers. In this first single-cell RNA-seq study of tetramer-sorted T cells from untreated celiac disease patients blood, we found that gluten-specific T cells showed distinct transcriptomic profiles consistent with activated effector memory T cells that shared features with Th1 and follicular helper T cells. Compared to non-specific cells, gluten-specific T cells showed differential expression of several genes involved in T-cell receptor signaling, translational processes, apoptosis, fatty acid transport, and redox potentials. Many of the gluten-specific T cells studied shared T-cell receptor with each other, indicating that circulating gluten-specific T cells belong to a limited number of clones. Moreover, the transcriptional profiles of cells that shared the same clonal origin were transcriptionally more similar compared with between clonally unrelated gluten-specific cells.

Study EGAS00001005517

Interethnic comparability in blood pressure GWAS

We carried out a genome-wide association and replication study for blood pressure in a two-stage approach (max N = 289,038) with a discovery stage sample of 130,777 East Asian individuals, identifying 19 new genetic loci. We found a significant genetic heterogeneity between East Asian and European-descent populations at several blood pressure loci, conforming to “a common ancestry-specific variant association model”. At 6 unique loci, distinct non-rare (or common) ancestry-specific variants co-localized within the same linkage disequilibrium block despite the significantly discordant direction of effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect sizes is 0.898 and 0.851 for systolic and diastolic blood pressure, respectively. Some of the ancestry-specific association signals were also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in the occurrence of ethnic differences in complex traits such as blood pressure.

Study EGAS00001002991

scRNA-seq of LN and lymphoma stroma

The activities of non-haematopoietic cells (NHCs), including mesenchymal stromal cells and endothelial cells, in lymphomas, reportedly underlie lymphomagenesis. However, understanding of lymphoma NHCs has been hampered by unexplained NHC heterogeneity, even in normal human lymph nodes (LNs). Here, we constructed a single-cell transcriptome atlas of >100,000 NHCs collected from 27 human samples, including LNs and various nodal lymphomas, revealing 30 distinct subclusters, including some that were previously unrecognized. Notably, this atlas was highly useful for comparative analysis with lymphoma NHCs, which revealed an unanticipated landscape of subcluster-specific changes in gene expression and interaction with malignant cells in follicular lymphoma NHCs, facilitating our understanding of stromal remodelling in lymphoma and potentially suggesting novel biomarkers. Our study largely updates NHC taxonomy in human LNs and pertains to analysis of disease status, providing a rich resource and deeper insights into LN and lymphoma biology and offering to advance lymphoma management and therapy.

Study EGAS00001005732

A living biobank of breast cancer organoids captures disease heterogeneity

Breast Cancer (BC) comprises multiple distinct subtypes that differ genetically, pathologically, and clinically. Xeno-transplantation and direct culturing of tumor tissue are increasingly used in drug development and personalized medicine strategies. Here, we describe a robust protocol for long-term culturing of human mammary epithelial organoids. Using this protocol, 101 BC organoid lines were generated, broadly recapitulating the diversity of the disease. BC organoid morphologies typically matched the histopathology, hormone receptor-, and HER2 status of the original tumor. DNA copy number variations as well as sequence changes were consistent within tumor-organoid pairs and largely retained even after extended passaging. BC organoids furthermore populated all major gene expression-based classification groups and allowed drug screens in vitro and upon xenotransplantation. This study describes a representative collection of well-characterized BC organoids available for cancer research and drug development, as well as a strategy to assess in vitro drug response in a personalized fashion.

Study EGAS00001002158

A microRNA-signature that correlates with cognition and is a target against cognitive decline

While some individuals age without pathological memory impairments, others develop age-associated cognitive diseases. Since changes in cognitive function develop slowly over time in these patients, they are often diagnosed at an advanced stage of molecular pathology, a time point when causative treatments fail. Thus, there is great need for the identification of inexpensive and minimal invasive approaches that could be used for screening with the aim to to identify individuals at risk for cognitive decline that can then undergo further diagnostics and eventually stratified therapies. In this study we use an integrative approach combining the analysis of human data and mechanistic studies in model systems to identify a circulating 3-microRNA signature that reflect key processes linked to neural homeostasis and informs about cognitive status. We furthermore provide evidence that expression changes of this signature represent multiple mechanisms de-regulated in the aging and diseased brain and are a suitable target for RNA therapeutics.

Study EGAS00001005627

Somatic_mutation_profiling_of_intestinal_crypts_from_IBD_Full_STDY

Following on from our pilot study we will investigate further the role that somatic mutations in intestinal stem cells play in IBD. We will use laser capture microdissection to ascertain epithelial cells from an individual crypts/vilus. We will extract DNA from these and use a new low-input material library prep methods to make accurate libraries for sequencing. We will perform 15X whole-genome sequencing of crypts biopsied from patients. Biopsies have been taken from inflammed and noninflammed patches to compare mutation rates and mutational signatures. We will also test if crypts from inflammed patches of a single patient are clonal (either within a given inflammed patch or across inflammed patches). We will quantify the rate of cancer driver mutations in inflammed and non-inflammed crypts. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Study EGAS00001003249

ENCORAFENIB COMBINED WITH BINIMETINIB FOR BRAFV600E-MUTATED RELAPSED/REFRACTORY MULTIPLE MYELOMA: THE PHASE II GMMG-BIRMA TRIAL (Hipo_K08K)

Activating BRAF mutations are rare events in multiple myeloma but have been shown to be promising therapeutic targets in small case studies. This multicenter phase II trial assessed the efficacy and safety of the BRAF/MEK inhibitors, encorafenib and binimetinib, in patients with relapsed/refractory multiple myeloma (RRMM) carrying an activating BRAFV600E mutation. Twelve RRMM patients with a median of five prior lines of therapy were enrolled. The study met its primary endpoint with 10 patients achieving at least a partial response according to IMWG criteria (overall response rate 83.3%). Responses occurred rapidly within the first cycle and deepened over time. The median progression-free survival (PFS) was 5.6 months and overall survival was 55% at 24 months. Genomic profiling revealed RAS mutations and structural variants involving the BRAF locus to be drivers of resistance to BRAF/MEK inhibition in RRMM. This trial demonstrates the value of translationally driven clinical trials in selected patient populations.

Study EGAS00001005973

Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 mutations. We performed whole-genome sequence (WGS) analysis of tumors from 22 TP53 mutation carriers. We observed somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous recombination genes as well as mutational signatures associated with prior chemotherapy. We identified near-ubiquitous early loss of heterozygosity of TP53, with gain of the mutant allele. This occurred earlier in these tumors compared to tumors with somatic TP53 mutations, suggesting the timing of this mark may distinguish germline from somatic TP53 mutations. Phylogenetic trees of tumor evolution, reconstructed from bulk and multi-region WGS, revealed that LFS tumors exhibit comparatively limited heterogeneity. Overall, our study delineates early copy number gains of mutant TP53 as a characteristic mutational process in LFS tumorigenesis, likely arising very early in life or in utero.years prior to tumor diagnosis.

Study EGAS00001005982

Exome sequencing of synchronous colorectal cancers

Approximately 4% of colorectal cancer (CRC) patients have at least two simultaneous cancers in the colon. Due to the shared environment, these synchronous CRCs (SCRCs) provide a unique setting to study colorectal carcinogenesis. Understanding whether these tumors are genetically similar or distinct is essential when designing therapeutic approaches. We performed exome sequencing of 47 primary cancers and corresponding normal samples from 23 patients. Additionally, we carried out a comprehensive mutational signature analysis to assess whether tumors had undergone similar mutational processes and the first immune cell score analysis (IS) of SCRC to analyze the interplay between immune cell invasion and mutation profile in both lesions of an individual. The tumor pairs shared only few mutations, favoring different mutations in known CRC genes and signaling pathways, and displayed variation in their signature content. Two tumor pairs had discordant mismatch repair statuses. In majority of the pairs, IS varied between primaries. Differences were not explained by any clinicopathological variable or mutation burden.

Study EGAS00001003474

Combined gene expression and digital pathology identifies molecular mediators of T cell exclusion and immune suppression in ovarian cancer

Close proximity between cytotoxic T lymphocytes and tumour cells is required for effective immunotherapy. However, what determines the spatial distribution of T cells in the tumour microenvironment is not well understood. Coupling digital pathology and transcriptome analysis on a large ovarian tumour cohort, we develop a machine learning approach to molecularly classify and characterize tumour-immune phenotypes. Our study identifies two important hallmarks characterizing T cell excluded tumours: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGFb and activated stroma. Furthermore, we identify TGFb as a key mediator of T cell exclusion. TGFb reduces MHC-I expression in ovarian cancer cells in vitro; TGFb also activates fibroblasts and induced extracellular matrix (ECM) production as a potential physical barrier to hinder T cell infiltration. Our findings indicate that targeting TGFb may represent a promising strategy to overcome T cell exclusion and improve clinical benefits of cancer immunotherapy.

Study EGAS00001003487

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