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Zhu, D.

Publications and source records attributed to Zhu, D..

At least 73 records · Page 4Linked to original sources
bioRxiv2023

Genomic locus of lncRNA-Gm26793 forms an inter-chromosomal molecular lock with Cubn to ensure proper stem cell differentiation and mouse embryogenesis

Inter-chromosomal interactions play a crucial role in 3D genome organization, yet the organizational principles and functional significances remain elusive. In general, long non-coding RNA (lncRNA) loci and transcripts are frequently associated with transcriptional programs modulated by long-range chromatin interactions. Here, we identified a novel lncRNA named Gm26793, which is abundantly distributed in the primitive streak and mesodermal cells of E7.5 mouse gastrula. Through genetic ablation of Gm26793, we observed a preferential responsiveness to primitive endoderm lineage during stem cell differentiation, as well as enhanced occurrence of transient and degenerative state cells in early mouse embryos when the cell fate segregates between epiblast and primitive endoderm. Mechanistically, we revealed the genomic locus of Gm26793, rather than the lncRNA transcript or adjacent gene governs the cell fate preference towards primitive endoderm. Concretely, Gm26793 locus (Chr 7) forms an inter-chromosomal molecular lock with Cubn (Chr 2), restraining the expression of Cubn and maintaining a natural epigenetic landscape, thus ensuring the proper lineage specification in vitro and in vivo. In order to reinforce this lock, CTCF and cohesin complex serves as a ring to fasten the inter-chromosomal contact. Overall, our study provides a clear paradigm that inter-chromosomal interaction collaborates with architectural factors to stabilize nuclear conformation and guarantee faithful gene expression during stem cell differentiation and mammalian embryogenesis.

developmental biology↗
bioRxiv2023

Prokaryotic microbial diversity analysis and metabolic function prediction of salt lakes on the Qinghai-Tibet Plateau

The Dong Taijinar Salt Lake (DT) and Xi Taijinar Salt Lake (XT) have been widely studied as mineral-rich areas. However, little is known about the composition and distribution of the microbial communities in these two lakes. In this study, metagenomics sequencing was used to analyze the diversity and potential functions of the microbial communities in DT and XT. According to our report, the salinity of DT (332.18-358.30 g/L) was 10 times higher than that of XT (20.09-36.83 g/L). Interestingly, the dominant domain in DT was Archaea (96.16%), while that in XT was Bacteria (93.09%). The distribution of Bacteria in the DT revealed 33 phyla and 1717 genera. The dominant genus in DT was Marinobacillus, which was positively correlated with total phosphorus content. There were four main phyla and 153 genera identified in the Archaea of DT. The most abundant Archaea genera in DT were Natronomonas (24.61%) and Halorubrum (23.69%), which were mainly positively correlated with the Na+, Ca2+, and Cl- contents. Similarly, there were 33 phyla and 1906 genera of Bacteria in XT, and Loktanella was the dominant genus. The archaeal taxonomy in XT mainly included four phyla and 149 genera. Proteobacteria and Euryarchaeota were the most abundant bacterial and archaeal phyla in the two salt lakes. Analysis of the halophilic mechanisms of the microorganisms identified in these two salt lakes revealed that the Bacteria in XT preferred to synthesize compatible solutes, whereas the Archaea in DT preferred a "salt-in" adaptation strategy in salt-stressed environments. IMPORTANCEThe Qinghai-Tibet Plateau is the origin of many lakes and mountains in China. Among them, the Dong Taijinar and Xi Taijinar salt lakes are important biological resources with unknown microbial community compositions and functional potentials. The results of this study revealed significant differences in the distribution of Bacteria and Archaea between the two salt lakes. Salinity mainly drives lower biodiversity and restricted bacterial growth and metabolism in the high-salinity and near-saturated Dong Taijinar Salt Lake. This study not only identifies the key microorganisms in two penetrating salt lakes, but also provides insights into the mechanisms of salinity tolerance and the unknown ecological functions of microorganisms in extreme environments.

microbiology↗
bioRxiv2023

Microbial biosensor for sensing and treatment of intestinal inflammation

Substantial synthetic biology efforts have been made to engineer biosensors to detect intestinal inflammation, however none target the most clinically accepted biomarker, calprotectin. To develop an in situ biosensor for calprotectin, we optimized a zinc uptake regulator (Zur) regulated promoter coupled with a memory circuit that can detect and record intestinal inflammation in vivo. The level of activation strongly correlates with calprotectin levels in the colon of two independent mouse models of colitis. Coupling of the biosensor with the production of the anti-inflammatory cytokine IL-10 allowed for the resolution of chemically induced colitis, demonstrating the ability of the biosensor to sense and respond to disease. This work highlights the utility of developing synthetic organisms for the diagnosis and treatment of intestinal disease using clinically validated biomarkers. One sentence summaryWe have optimized a microbial biosensor to detect and respond to the clinically relevant intestinal inflammation biomarker calprotectin.

synthetic biology↗
bioRxiv2023

The ChickenGTEx pilot analysis: a reference of regulatory variants across 28 chicken tissues

Chicken is a valuable model for understanding fundamental biology, vertebrate evolution and diseases, as well as a major source of nutrient-dense and lean-protein-enriched food globally. Although it is the first non-mammalian amniote genome to be sequenced, the chicken genome still lacks a systematic characterization of functional impacts of genetic variants. Here, through integrating 7,015 RNA-Seq and 2,869 whole-genome sequence data, the Chicken Genotype- Tissue Expression (ChickenGTEx) project presents the pilot reference of regulatory variants in 28 chicken tissue transcriptomes, including millions of regulatory effects on primary expression (including protein-coding genes, lncRNA and exon) and post-transcriptional modifications (alternative splicing and 3 untranslated region alternative polyadenylation). We explored the tissue-sharing and context-specificity of these regulatory variants, their underlying molecular mechanisms of action, and their utility in interpreting adaptation and genome-wide associations of 108 chicken complex traits. Finally, we illustrated shared and lineage-specific features of gene regulation between chickens and mammals, and demonstrated how the ChickenGTEx resource can further assist with translating genetic findings across species. One-Sentence SummaryThe ChickenGTEx provides a multi-tissue reference of regulatory variants for chicken genetics and genomics, functional genomics, precision breeding, veterinary medicine, vertebrate evolution and even human biomedicine.

genetics↗
bioRxiv2023

56Fe ion exposure increases the incidence of lung and brain tumors at a similar rate in male and female mice

The main deterrent to long-term space travel is the risk of Radiation Exposure Induced Death (REID). The National Aeronautics and Space Administration (NASA) has adopted Permissible Exposure Levels (PELs) to limit the probability of REID to 3% for the risk of death due to radiation-induced carcinogenesis. The most significant contributor to current REID estimates for astronauts is the risk of lung cancer. Recently updated lung cancer estimates from Japans atomic bomb survivors showed that the excess relative risk of lung cancer by age 70 is roughly four-fold higher in females compared to males. However, whether sex differences may impact the risk of lung cancer due to exposure to high charge and energy (HZE) radiation is not well studied. Thus, to evaluate the impact of sex differences on the risk of solid cancer development post-HZE radiation exposure, we irradiated Rbfl/fl; Trp53fl/+ male and female mice infected with Adeno-Cre with various doses of 320 kVp X-rays or 600 MeV/n 56Fe ions and monitored them for any radiation-induced malignancies. We observed that lung adenomas/carcinomas and esthesioneuroblastomas (ENBs) were the most common primary malignancies in X-ray and 56Fe ion-exposed mice, respectively. In addition, 1 Gy 56Fe ion exposure compared to X-rays led to a significantly higher incidence of lung adenomas/carcinomas (p=0.02) and ENBs (p<0.0001). However, we did not find a significantly higher incidence of any solid malignancies in female mice as compared to male mice, regardless of radiation quality. Furthermore, gene expression analysis of ENBs suggested a distinct gene expression pattern with similar hallmark pathways altered, such as MYC targets and MTORC1 signaling, in X-ray and 56Fe ion-induced ENBs. Thus, our data revealed that 56Fe ion exposure significantly accelerated the development of lung adenomas/carcinomas and ENBs compared to X-rays, but the rate of solid malignancies was similar between male and female mice, regardless of radiation quality.

cancer biology↗
bioRxiv2023

Optimizing Cell Therapy by Sorting Cells with High Extracellular Vesicle Secretion

Critical challenges remain in clinical translation of extracellular vesicle (EV)-based therapeutics due to the absence of methods to enrich cells with high EV secretion. Current cell sorting methods are limited to surface markers that are uncorrelated to EV secretion or therapeutic potential. We developed a nanovial technology for enrichment of millions of single cells based on EV secretion. This approach was applied to select mesenchymal stem cells (MSCs) with high EV secretion as therapeutic cells for improving treatment. The selected MSCs exhibited distinct transcriptional profiles associated with EV biogenesis and vascular regeneration and maintained high levels of EV secretion after sorting and regrowth. In a mouse model of myocardial infarction, treatment with high-secreting MSCs improved heart functions compared to treatment with low-secreting MSCs. These findings highlight the therapeutic importance of EV secretion in regenerative cell therapies and suggest that selecting cells based on EV secretion could enhance therapeutic efficacy.

bioengineering↗
bioRxiv2023

Nature-based solutions in Australia: a systematic quantitative literature review of terms, application and policy relevance

Nature-based Solutions (NbS) are emerging as an approach to sustainable environmental management and addressing environmental and social issues in ways that benefit human well-being and biodiversity. NbS have been applied to social-environmental challenges such as climate change and urbanization, but with diverse conceptualisations and applications that may impact their effectiveness and broader uptake. Much of the literature and implementation of NbS has emerged from Europe and though NbS use is rising in Australia, the context is unclear. This systematic quantitative literature review aims to understand Nature-based Solutions in an Australian context. Here we explore the meaning and practical uses of NbS in Australia, through three research questions: In Australia, 1) what is meant by the term nature-based solutions? 2) what socio-ecological challenges do NbS aim to address and how? 3) are there gaps in NbS research and policy application that are hindering uptake of NbS approaches? We show that in Australia, local governments are using NbS in urban planning to address the compounding challenges brought on by climate change in the human-environment interfaces. However, there is no consensus on NbS definitions and approaches, research is focussed on urban areas and problems, and NbS implementation follows a bottom-up, localised pattern without an integrated policy framework. Based on these findings, we provide recommendations for improving the implementation of NbS in Australia including: 1) a consistency of NbS definition and awareness of NbS approaches; 2) interdisciplinary and interdepartmental collaboration on NbS methods and effectiveness and; 3) an integrated policy framework supporting NbS nationwide.

ecology↗
bioRxiv2023

Evolution of a Functionally Intact but Antigenically Distinct DENV Fusion Loop

A hallmark of Dengue virus (DENV) pathogenesis is the potential for antibody-dependent enhancement, which is associated with deadly DENV secondary infection, complicates the identification of correlates of protection, and negatively impacts the safety and efficacy of DENV vaccines. ADE is linked to antibodies targeting the fusion loop (FL) motif of the envelope protein, which is completely conserved in mosquito-borne flaviviruses and required for viral entry and fusion. In the current study, we utilized saturation mutagenesis and directed evolution to engineer a functional variant with a mutated FL (D2-FL) which is not neutralized by FL-targeting monoclonal antibodies. The FL mutations were combined with our previously evolved prM cleavage site to create a mature version of D2-FL (D2-FLM), which evades both prM- and FL-Abs but retains sensitivity to other type-specific and quaternary cross-reactive (CR) Abs. CR serum from heterotypic (DENV4) infected non-human primates (NHP) showed lower neutralization titers against D2-FL and D2-FLM than isogenic wildtype DENV2 while similar neutralization titers were observed in serum from homotypic (DENV2) infected NHP. We propose D2-FL and D2-FLM as valuable tools to delineate CR Ab subtypes in serum as well as an exciting platform for safer live attenuated DENV vaccines suitable for naive individuals and children.

microbiology↗
bioRxiv2022

T cell development is regulated by high fidelity replication of mitochondrial DNA

One of the most proliferative periods for T cells occurs during their development in the thymus. Increased DNA replication can result in increased DNA mutations in the nuclear genome, but also in mitochondrial genomes. A high frequency of mitochondrial DNA mutations can lead to abnormal mitochondrial function and have negative implications on human health. Furthermore, aging is accompanied by an increase in such mutations through oxidative damage and replication errors. Increased mitochondrial DNA mutations cause loss of mitochondrial protein function, and decrease energy production, substrates, and metabolites. Here we have evaluated the effect of increased mitochondrial DNA mutations on T cell development in the thymus. Using mice carrying a mutant mitochondrial DNA polymerase {gamma} (PolG) that causes increased mitochondrial DNA mutations, we show that high fidelity replication of mitochondrial DNA is pivotal for proper T cell development. Reducing the fidelity of mitochondrial DNA replication results in a premature age-dependent reduction in the total number of CD4/CD8 double negative and double positive thymocytes. Analysis of mitochondrial density in thymocyte subpopulations suggests that this may be due to reduced proliferation in specific double negative stages. Taken together, this work suggests that T cell development is regulated by the ability of mitochondria to faithfully replicate their DNA.

immunology↗
bioRxiv2022

Flagellin modulates regulation of Clostridiodes difficile pathogenesis in the absence of motility

Mutations affecting Clostridioides difficile flagellin (FliC) have been shown to be hypervirulent in animal models and display increased toxin production and alterations in central metabolism. The regulation of flagellin levels in bacteria is governed by a tripartite regulatory network involving fliC, fliW, and csrA, which creates a feedback system to regulate flagella production. Through genomic analysis of C. difficile clade 5 strains (non-motile), we identified they have jettisoned many of the genes required for flagellum biosynthesis yet retain the major flagellin gene fliC and regulatory gene fliW. We therefore investigated the roles of fliC, fliW, and csrA in the clade 5 ribotype 078 strain C. difficile 1015, which lacks flagella and is non-motile. Analysis of mutations in fliC, fliW, and csrA (and all combinations) on C. difficile pathogenesis indicated that FliW plays a central role in C. difficile virulence as animals infected with strains carrying a deletion of fliW showed decreased survival and increased disease severity. These in vivo findings were supported by in vitro studies showing that mutations impacting the activity of FliW showed increased toxin production. We further identified that FliW can interact with the toxin positive regulator TcdR, indicating that modulation of toxin production via FliW occurs by sequestering TcdR from activating toxin transcription. Furthermore, disruption of the fliC-fliW-csrA network results in significant changes in carbon source utilization and sporulation. This work highlights that key proteins involved in flagellar biosynthesis retain their regulatory roles in C. difficile pathogenesis and physiology independent of their functions in motility. IMPORTANCEC. difficile is a leading cause of nosocomial antibiotic-associated diarrhea in developed countries with many known virulence factors. In several pathogens, motility and virulence are intimately linked by regulatory networks that allow coordination of these processes in pathogenesis and physiology. Regulation of C. difficle toxin production by FliC has been demonstrated in vitro and in vivo and has been proposed to link motility and virulence. Here we show that clinically important, non-motile C. difficile strains have conserved FliC and regulatory partners FliW and CsrA, despite lacking the rest of the machinery to produce functional flagella. Our work highlights a novel role for flagellin outside of its role in motility and FliW in the pathogenesis and physiology of C. difficile.

microbiology↗
bioRxiv2022

Proteomics Characteristics Reveal the Risk of T1 Colorectal Cancer Metastasis to Lymph Nodes

BackgroundThe presence of lymph node metastasis (LNM) affects treatment strategy decisions in T1NxM0 colorectal cancer (CRC), but the currently used clinicopathological-based risk stratification cannot predict LNM accurately. In this study, we established a classifier for predicting LNM in T1 CRC. MethodsWe detected proteins in formalin-fixed paraffin-embedded (FFPE) tumor samples from 143 LNM-negative and 78 LNM-positive patients with T1 CRC and revealed changes in molecular and biological pathways by label-free LC-MS/MS. An effective prediction model was built and validated in a training cohort (N=132) and two validation cohorts (VC1, N=42; VC2, N=47) by machine learning. We further built a simplified classifier with 9 proteins. The expression patterns of 13 proteins were confirmed by immunohistochemistry, and the IHC score of 5 proteins were used to build a IHC predict model. ResultPatients with or without LNM have different molecular signatures. The 55-proteins prediction model achieved an impressive AUC of 1.00 in the training cohort, 0.96 in VC1 and 0.93 in VC2. The 9-protein classifier achieved an AUC of 0.824, and the calibration plot was excellent. We found that 5 biomarkers could predict LNM by the IHC score, with an AUC of 0.825. RHOT2 silence significantly enhanced migration and invasion of colon cancer cells. ConclusionsOur study explored the mechanism of metastasis in T1 CRC and can be used to facilitate the individualized prediction of LNM in patients with T1 CRC, which may provide a guidance for clinical practice in T1 CRC.

cancer biology↗
bioRxiv2022

Endothelial TIE1 restricts angiogenic sprouting to coordinate vein assembly in synergy with its homologue TIE2

ObjectiveVascular growth followed by vessel specification is crucial for the establishment of a hierarchical blood vascular network. We have here investigated mechanisms underlying venogenesis, particularly the molecular control over venous fate acquisition during vascular development. Approach and ResultsWe analyzed the function of TIE1 as well as its synergy with TIE2 in the regulation of vein formation by employing genetic mouse models targeting Tie1 and Tek. Cardinal vein growth appeared normal in TIE1 deficient mice, whereas TIE2 deficiency altered the identity of cardinal vein endothelial cells with the aberrant expression of DLL4. Interestingly, the parallel growth of murine cutaneous veins along with arteries, which was initiated at approximately embryonic day 13.5, was retarded in mice lack of TIE1. Tie1 deletion disrupted also venous integrity, displaying increased sprouting angiogenesis and vascular bleeding. Abnormal venous sprouts with defective arteriovenous alignment were also observed in the mesenteries of Tie1 deleted mice. Mechanistically, TIE1 deficiency resulted in the decreased expression of venous regulators including TIE2 while angiogenic regulators were upregulated. The alteration of TIE2 level by TIE1 insufficiency was further confirmed by the siRNA-mediated knockdown of Tie1 in cultured endothelial cells. Additionally, combining the endothelial deletion of Tie1 with one null allele of Tek resulted in a progressive increase of vein-associated angiogenesis leading to the formation of vascular tufts in retinas, whereas the loss of Tie1 alone produced only a relatively mild venous defect. ConclusionsFindings from this study imply that TIE1 and TIE2 act in a synergistic manner to restrict sprouting angiogenesis during vein formation.

developmental biology↗
bioRxiv2022

A bioengineered probiotic for the oral delivery of a peptide Kv1.3 channel blocker to treat rheumatoid arthritis

Engineered microbes for the delivery of biologics is a promising avenue for the treatment of various conditions such as chronic inflammatory disorders and metabolic disease. In this study, we developed a genetically engineered probiotic delivery system that delivers the small molecular biologic to the intestinal tract with high efficacy and minimized side effects. We constructed an inducible system in the probiotic Lactobacillus reuteri to secret functional Kv1.3 potassium blocker ShK-235 (LrS235). We show that LrS235 is capable of blocking Kv1.3 currents and preferentially inhibiting human T effector memory (TEM) cells proliferation in vitro. A single oral gavage of healthy rats with LrS235 resulted in adequate functional ShK-235 in the circulation to reduce inflammation in a delayed-type hypersensitivity model of atopic dermatitis mediated by TEM cells. Furthermore, the daily oral gavage of LrS235 dramatically reduced clinical signs of disease and joint inflammation in rats with a model of rheumatoid arthritis without eliciting immunogenicity against ShK-235. This work demonstrates the efficacy of using probiotic L. reuteri as a novel oral delivery platform for the small molecule ShK-235, and provides a efficacious strategy to deliver other biologics with great translational potential. Significance StatementNew therapeutics that combine efficacy with limited side effects and can be delivered non-invasively are needed to adequately treat patients with rheumatoid arthritis (RA) and other autoimmune diseases. Kv1.3 channel-expressing CCR7- effector memory T (TEM) lymphocytes are significant players in the pathogenesis of multiple autoimmune diseases and blocking Kv1.3 reduces disease severity in rat models of RA and patients with plaque psoriasis. However, peptide therapeutics require repeated injections, reducing patient compliance. We used a bioengineered Lactobacillus reuteri as an oral delivery method of a Kv1.3 blocker for immunomodulation in rat models of atopic dermatitis and RA. This study demonstrates a novel approach for the non-invasive delivery of peptide-based therapeutics for the oral treatment of chronic inflammatory diseases.

synthetic biology↗
bioRxiv2022

Disruption of CFAP418 interaction with lipids causes abnormal membrane-associated cellular processes in retinal degenerations

Syndromic ciliopathies and retinal degenerations are large heterogeneous groups of genetic diseases. CFAP418 is a causative gene of both disorders, and its protein sequence is evolutionarily conserved. However, the pathogenic mechanism caused by CFAP418 mutations is largely unknown. Here, we employed affinity purification coupled with mass spectrometry and quantitative lipidomic, proteomic, and phosphoproteomic approaches to address the molecular function of CFAP418 in mouse retinas. We showed that CFAP418 bound to lipid metabolism precursor phosphatidic acid (PA) and mitochondrion-specific lipid cardiolipin but did not form a tight and static complex with proteins. Loss of Cfap418 led to membrane lipid imbalance and protein-membrane association alteration, which subsequently caused mitochondrial defects and membrane remodeling abnormalities in multiple vesicular trafficking pathways. Loss of Cfap418 also increased the activity of PA-binding protein kinase C. Our results indicate that membrane lipid imbalance is a new pathological mechanism underlying syndromic ciliopathies and retinal degenerations, which is associated with other known causative genes for these diseases, such as RAB28 and BBS genes.

cell biology↗
bioRxiv2022

Long non coding RNA L13Rik promotes high glucose-induced mesangial cell injury by regulating miR-2861/CDKN1B axis

Diabetic nephropathy (DN) is a frequent and severe microvascular complication of diabetes. Glomerular mesangial cell (MC) injury occurs at the initial phase of DN and acts as a critical role in the pathogenesis of DN. Given the importance of long non-coding RNA (lncRNA) in regulating MC hyperplasia and extracellular matrix (ECM) accumulation, it is essential to identify functional lncRNAs during MC injury. Here a novel lncRNA, C920021L13Rik (L13Rik for short), was identified to up-regulated in DN progression. The expression of L13Rik in DN patients and diabetic rats was assessed using quantitative real-time PCR (qRT-PCR), and the function of L13Rik on regulating HG-induced MC injury was assessed using cell counting kit-8 (CCK-8) and western blot assay to analyze MC viability and ECM accumulation. We found that L13Rik level was significantly increased while miR-2861 level was significantly decreased in peripheral blood of DN patients, renal tissues of diabetic rats, and HG-treated MCs. Functionally, both L13Rik depletion and miR-2861 overexpression effectively reduced HG-induced MC survival, ECM accumulation, and cell hypertrophy. Mechanistically, L13Rik functioned as a competing endogenous RNA (ceRNA) to sponge miR-2861, resulting in the de-repression of its target cyclin-dependent kinase inhibitor 1B (CDKN1B), a gene known to accelerate MC injury. Collectively, the current results demonstrate that up-regulated L13Rik is correlated with DN, and may be a hopeful therapeutic target for DN.

cancer biology↗
bioRxiv2022

Spinning Disk Multifocal Microscopy for Dynamic Arbitrarily Shaped Surface Imaging at Centimetre Scale and Micrometre Resolution

The large-scale fluorescence microscopy has enabled the observation of dynamic physiological activities at the single cellular level across the mouse cortex, such as distributed neuronal population representations. However, video-rate high-resolution microscopy at sophisticated biological surfaces in nature keeps a challenging task for the tradeoff between the speed, resolution, and field of view. Here we propose Spinning Disk Multifocal Microscopy (SDiM) for arbitrarily shaped surfaces, which enables imaging at centimeter field-of-view, micrometer resolution and up to 30 frames per second across the depth range of 450 {micro}m. We apply this technique in various microscopic systems, including customized macroscopic systems and the Real-time Ultra-large-Scale imaging at High resolution macroscopy (RUSH), in both the reflective mode and the fluorescence mode, and in the study of cortex-wide single-neuron imaging and immune cell tracking. SDiM provides an opportunity for studying the cortex-wide multi-scale cellular interactions in biological tissues.

bioengineering↗
bioRxiv2022

The infiltration pattern of microenvironmental cells and different immune escape mechanisms in colorectal cancer

BackgroundThe tumour microenvironment (TME) plays a crucial role in tumour progression and metastasis. However, the infiltration pattern of TME cells in CRC samples and the immune escape mechanism underneath have not been studied sufficiently. MethodsTranscriptomic data from public datasets were retrieved online. In total, 1802 samples from the microarray dataset and 619 samples from the TCGA dataset were enrolled. The ssGSEA algorithm and unsupervised clustering were used for TME cells infiltration speculation and infiltration pattern recognition. ResultsCRC samples can be classified into three distinct TME cell subtypes. Subtype 1, the immune-active subtype, was characterised by high infiltration of activated adaptive immune cells. Subtype 2, the immune-desert subtype, featured high tumour purity and low infiltration of immune and stromal cells. And subtype 3, stroma-rich subtype, had high infiltration of stromal cells. The stroma-rich subtype conferred a significantly worse prognosis. Three subtypes had different immune escape mechanisms. The immune-active subtype has the highest immune checkpoint expression level. In comparison, the immune-desert subtype had the lowest immunogenicity and the defective antigen presentation. And the stroma-rich subtype lacked activated immune cells. ConclusionsDistinct TME cell subtypes and immune escape mechanisms may provide inspiration and direction for further researches on CRC immunotherapy.

cancer biology↗