Prognositic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma

Objective:Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents,with a poor prognosis.Anchorage-dependent cell death(anoikis)has been proven to be indispensable in tumor metastasis,regulating the migration and adhesion of tumor cells at the primary site.However,as a type of programmed cell death,anoikis is rarely studied in osteosarcoma,especially in the tumor immune microenvironment.This study aims to clarify prognostic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma.Methods:Anoikis-related genes(ANRGs)were obtained from GeneCards.Clinical information and ANRGs expression profiles of osteosarcoma patients were sourced from the therapeutically applicable research to generate effective therapies and Gene Expression Omnibus(GEO)databases.ANRGs highly associated with tumor immune microenvironment were identified by the estimate package and the weighted gene coexpression network analysis(WGCNA)algorithm.Machine learning algorithms were performed to construct long-term survival predictive strategy,each sample was divided into high-risk and low-risk subgroups,which was further verified in the GEO cohort.Finally,based on single-cell RNA-seq from the GEO database,analysis was done on the function of signature genes in the osteosarcoma tumor microenvironment.Results:A total of 51 hub ANRGs closely associated with the tumor microenvironment were identified,from which 3 genes(MERTK,BNIP3,S100A8)were selected to construct the prognostic model.Significant differences in immune cell activation and immune-related signaling pathways were observed between the high-risk and low-risk groups based on tumor microenvironment analysis(all P<0.05).Additionally,characteristic genes within the osteosarcoma microenvironment were identified in regulation of intercellular crosstalk through the GAS6-MERTK signaling pathway.Conclusion:The prognostic model based on ANRGs and tumor microenvironment demonstrate good predictive power and provide more personalized treatment options for patients with osteosarcoma.

DNA Damage-driven Inflammatory Cytokines:Reprogramming of Tumor Immune Microenvironment and Application of Oncotherapy

DNA damage occurs across tumorigenesis and tumor development.Tumor intrinsic DNA damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orchestrate the tumor immune microenvironment(TIME)and dominate tumor progression.Accumulating evidence documents that multiple signaling pathways,including cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)and ataxia telangiectasia-mutated protein/ataxia telangiectasia and Rad3-related protein(ATM/ATR),are activated downstream of DNA damage and they are associated with the secretion of diverse cytokines.These cytokines possess multifaced functions in the anti-tumor immune response.Thus,it is necessary to deeply interpret the complex TIME reshaped by damaged DNA and tumor-derived cytokines,critical for the development of effective tumor therapies.This manuscript comprehensively reviews the relationship between the DNA damage response and related cytokines in tumors and depicts the dual immunoregulatory roles of these cytokines.We also summarize clinical trials targeting signaling pathways and cytokines associated with DNA damage and provide future perspectives on emerging technologies.

Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS

The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking.To address this gap,we conducted a study aiming to investigate this association and identify relevant biomarkers.We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment,biological activity,and the immune microenvironment.Additionally,we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies(GWASs)involving both East Asian(7062 cases and 195745 controls)and European(24476 cases and 23073 controls)populations.We employed mediation analysis to infer the causal pathway,and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells.Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1(FEN1)gene were significantly enriched in colorectal tumor tissues,compared with normal tissues.Moreover,a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer(odds ratio=0.94,95%confidence interval:0.90–0.97,P_(meta)=4.70×10^(-9)).Importantly,we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors,and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication.In conclusion,this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity,expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.

Mechanisms of tumor immunosuppressive microenvironment formation in esophageal cancer

As a highly invasive malignancy,esophageal cancer(EC)is a global health issue,and was the eighth most prevalent cancer and the sixth leading cause of cancerrelated death worldwide in 2020.Due to its highly immunogenic nature,emerging immunotherapy approaches,such as immune checkpoint blockade,have demonstrated promising efficacy in treating EC;however,certain limitations and challenges still exist.In addition,tumors may exhibit primary or acquired resistance to immunotherapy in the tumor immune microenvironment(TIME);thus,understanding the TIME is urgent and crucial,especially given the importance of an immunosuppressive microenvironment in tumor progression.The aim of this review was to better elucidate the mechanisms of the suppressive TIME,including cell infiltration,immune cell subsets,cytokines and signaling pathways in the tumor microenvironment of EC patients,as well as the downregulated expression of major histocompatibility complex molecules in tumor cells,to obtain a better understanding of the differences in EC patient responses to immunotherapeutic strategies and accurately predict the efficacy of immunotherapies.Therefore,personalized treatments could be developed to maximize the advantages of immunotherapy.

Hepatocellular carcinoma immune microenvironment and check point inhibitors-current status

Hepatocellular carcinoma(HCC)is the most common primary tumor of the liver and has a high mortality rate.The Barcelona Clinic Liver Cancer staging system in addition to tumor staging also links the modality of treatment available to a particular stage.The recent description of the tumor microenvironment(TME)in HCC has provided a new concept of immunogenicity within the HCC.Virusrelated HCC has been shown to be more immunogenic with higher expression of cytotoxic T lymphocytes and decreased elements for immunosuppression such as regulatory T cells.This immunogenic milieu provides a better response to immunotherapy especially immune checkpoint inhibitors(ICIs).In addition,the recent data on combining locoregional therapies and other strategies may convert the less immunogenic state of the TME towards higher immunogenicity.Therefore,data are emerging on the use of combinations of locoregional therapy and ICIs in unresectable or advanced HCC and has shown better survival outcomes in this difficult population.

The lactylation index predicts the immune microenvironment and prognosis of pan-cancer patients

Background:Protein lactylation is a new way for the“metabolic waste”lactic acid to perform novel functions.Nevertheless,our understanding of the contribution of protein lactylation to both tumor progression and therapeutic interventions remains imited.The construction of a scoring system for lactylation to predict the prognosis of pancancer patients and to evaluate the tumor immune microenvironment(TIME)would improve our understanding of the clinical significance of lactylation.Methods:Consensus clustering analysis of lactylation-related genes was used to cluster 177 pancreatic adenocarcinoma(PAAD)patients.Subsequently,a scoring system was developed using the least absolute shrinkage and selection operator(LASSO)regression.Internal validation and external validation were both conducted to assess and confirm the predictive accuracy of the scoring system.Finally,leucine rich repeat containing 1(LRRC1),a newly discovered lactylation-related gene,was analyzed in PAAD in vitro.Results:Utilizing the profiles of 332 lactylation-related genes,a total of 177 patients with PAAD were segregated into two distinct groups.LacCluster^(high) patients had a poorer prognosis than LacCluster^(low) patients.Through the differential analysis between the LacCluster^(high) and LacCluster^(low) groups,we identified additional genes associated with lactylation.These genes were then integrated to construct the LacCluster-enhanced system,which enabled more accurate prognosis prediction for patients with PAAD.Then,a lactylation index containing three genes(LacI-3)was constructed using LASSO regression.This was done to enhance the usability of the LacCluster-enhanced system in the clinic.Compared to those in the LacI-3^(high) subgroup,patients in the LacI-3^(low) subgroup exhibited increased expression of immune checkpoint-related genes,more immune cell infiltration,lower tumor mutation burdens,and better prognoses,indicating a“hot tumor”phenotype.Moreover,knocking down the expression of LRRC1,the hub gene in the LacI-3 scoring system,inhibited PAAD cell invasion,migration,and proliferation in vitro.Ultimately,the significance of LacI-3 across cancers was confirmed.Conclusion:Our findings strongly imply that protein lactylation may represent a new approach to diagnosing and treating malignant tumors.

Physical exercise reverses immuno-cold tumor microenvironment via inhibiting SQLE in non-small cell lung cancer

Dear Editor,Physical exercise has been shown to be associated with reduced cancer incidence and cancer-associated mortality[1,2],but the underlying mechanisms are obscure.Immunometabolic regulation has emerged as one of the most prominent mechanisms explaining the effects of exercise on cancer[1,2].Physical exercise primarily lowers blood cholesterol and triglycerides,and protects against cardiovascular diseases[3].However,whether physical exercise can modulate cholesterol metabolism in tumor cells is currently unknown.

Immunosuppressive tumor microenvironment in gastric signet-ring cell carcinoma

Gastric signet-ring cell carcinoma(GSRCC)is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis.Studies have shown that early GSRCC has a good prognosis,while advanced GSRCC is insensitive to radiotherapy,chemotherapy or immune checkpoint blockade therapy.With technological advancement of single-cell RNA sequencing analysis and cytometry by time of flight mass cytometry,more detailed atlas of tumor microenvironment(TME)in GSRCC and its association with prognosis could be investigated extensively.Recently,two single-cell RNA sequencing studies revealed that GSRCC harbored a unique TME,manifested as highly immunosuppressive,leading to high immune escape.The TME of advanced GSRCC was enriched for immunosuppressive factors,including the loss of CXCL13+-cluster of differentiation 8+-Tex cells and declined clonal crosstalk among populations of T and B cells.In addition,GSRCC was mainly infiltrated by follicular B cells.The increased proportion of SRCC was accompanied by a decrease in mucosaassociated lymphoid tissue-derived B cells and a significant increase in follicular B cells,which may be one of the reasons for the poor prognosis of GSRCC.By understanding the relationship between immunosuppressive TME and poor prognosis in GSRCC and the underlying mechanism,more effective immunotherapy strategies and improved treatment outcomes of GSRCC can be anticipated.

SR-BI expression regulates the gastric cancer tumor immune microenvironment and is associated with poor prognosis

Aim:Scavenger receptor class B,type I(SR-BI)is an integral plasma membrane protein that has been reported to be overexpressed in various malignancies,such as renal cancer,breast cancer,and prostate cancer,and is an independent prognostic factor.However,the clinical value and expression of SR-BI in GC are unknown.Our research aimed to explore the role of SR-BI in combination with immune markers as a diagnostic and prognostic marker for gastric cancer(GC).Methods:GC tissues,paracancerous tissues,and clinicopathological data of 149 patients were collected.The expression level of SR-BI,Tumor-infiltrating lymphocytes(TILs),and PD-L1 were evaluated by immunohistochemistry(IHC).The associations of the SR-BI staining intensity with clinicopathological features and immune markers were determined by the chi-square test.Univariate and multivariate COX regression analyses were used to evaluate independent prognostic factors.Kaplan–Meier analyses were performed to plot the survival curve.Results:Our results indicated that SR-BI was expressed at higher levels in tumor tissues than in adjacent paracancerous tissues(p<0.001),and patients with high levels of SR-BI expression had a worse prognosis.Univariate and multivariate analyses revealed that high SR-BI expression was an independent factor for poor prognosis.The chi-square test determined that the expression of SR-BI was negatively correlated with CD4+T cells and CD8+T cells(CD4+T cells,p=0.013;CD8+T cells,p=0.021),and positively correlated with PD-L1(p=0.022).Finally,survival analysis revealed that CD4+T cells were associated with the prognosis of GC patients(p=0.019),and the combined survival analysis of SR-BI and CD4+T cells was also statistically significant(p=0.030).Conclusion:SR-BI is highly expressed in GC tissue and associated with poor prognosis.Moreover,SR-BI can also regulate the GC tumor immune microenvironment.

Prediction of Tumor Microenvironment Characteristics and Treatment Response in Lung Squamous Cell Carcinoma by Pseudogene OR7E47P-related Immune Genes

Objective Pseudogenes are initially regarded as nonfunctional genomic sequences,but some pseudogenes regulate tumor initiation and progression by interacting with other genes to modulate their transcriptional activities.Olfactory receptor family 7 subfamily E member 47 pseudogene(OR7E47P)is expressed broadly in lung tissues and has been identified as a positive regulator in the tumor microenvironment(TME)of lung adenocarcinoma(LUAD).This study aimed to elucidate the correlation between OR7E47P and tumor immunity in lung squamous cell carcinoma(LUSC).Methods Clinical and molecular information from The Cancer Genome Atlas(TCGA)LUSC cohort was used to identify OR7E47P-related immune genes(ORIGs)by weighted gene correlation network analysis(WGCNA).Based on the ORIGs,2 OR7E47P clusters were identified using non-negative matrix factorization(NMF)clustering,and the stability of the clustering was tested by an extreme gradient boosting classifier(XGBoost).LASSO-Cox and stepwise regressions were applied to further select prognostic ORIGs and to construct a predictive model(ORPScore)for immunotherapy.The Botling cohorts and 8 immunotherapy cohorts(the Samstein,Braun,Jung,Gide,IMvigor210,Lauss,Van Allen,and Cho cohorts)were included as independent validation cohorts.Results OR7E47P expression was positively correlated with immune cell infiltration and enrichment of immune-related pathways in LUSC.A total of 57 ORIGs were identified to classify the patients into 2 OR7E47P clusters(Cluster 1 and Cluster 2)with distinct immune,mutation,and stromal programs.Compared to Cluster 1,Cluster 2 had more infiltration by immune and stromal cells,lower mutation rates of driver genes,and higher expression of immune-related proteins.The clustering performed well in the internal and 5 external validation cohorts.Based on the 7 ORIGs(HOPX,STX2,WFS,DUSP22,SLFN13,GGCT,and CCSER2),the ORPScore was constructed to predict the prognosis and the treatment response.In addition,the ORPScore was a better prognostic factor and correlated positively with the immunotherapeutic response in cancer patients.The area under the curve values ranged from 0.584 to 0.805 in the 6 independent immunotherapy cohorts.Conclusion Our study suggests a significant correlation between OR7E47P and TME modulation in LUSC.ORIGs can be applied to molecularly stratify patients,and the ORPScore may serve as a biomarker for clinical decision-making regarding individualized prognostication and immunotherapy.

Diagnostic Value of GDF10 for the Tumorigenesis and Immune Infiltration in Lung Squamous Cell Carcinoma

Objective:Lung squamous cell carcinoma(LUSC)is associated with a low survival rate.Evidence suggests that bone morphogenetic proteins(BMPs)and their receptors(BMPRs)play crucial roles in tumorigenesis and progression.However,a comprehensive analysis of their role in LUSC is lacking.Our study aimed to explore the relationship between BMPs/BMPRs expression levels and the tumorigenesis and prognosis of LUSC.Methods:The“R/Limma”package was utilized to analyze the differential expression characteristics of BMPs/BMPRs in LUSC,using data from TCGA,GTEx,and GEO databases.Concurrently,the“survminer”packages were employed to investigate their prognostic value and correlation with clinical features in LUSC.The core gene associated with LUSC progression was further explored through weighted gene correlation network analysis(WGCNA).LASSO analysis was conducted to construct a prognostic risk model for LUSC.Clinical specimens were examined by immunohistochemical analysis to confirm the diagnostic value in LUSC.Furthermore,based on the tumor immune estimation resource database and tumor-immune system interaction database,the role of the core gene in the tumor microenvironment of LUSC was explored.Results:GDF10 had a significant correlation only with the pathological T stage of LUSC,and the protein expression level of GDF10 decreased with the tumorigenesis of LUSC.A prognostic risk model was constructed with GDF10 as the core gene and 5 hub genes(HRASLS,HIST1H2BH,FLRT3,CHEK2,and ALPL)for LUSC.GDF10 showed a significant positive correlation with immune cell infiltration and immune checkpoint expression.Conclusion:GDF10 might serve as a diagnostic biomarker reflecting the tumorigenesis of LUSC and regulating the tumor immune microenvironment to guide more effective treatment for LUSC.

Tumor-derived DEFB1 induces immune tolerance by inhibiting maturation of dendritic cell and impairing CD8+T cell function in esophageal squamous cell carcinoma

Objective:CD8+T cells are the key effector cells in the anti-tumor immune response.The mechanism underlying the infiltration of CD8+T cells in esophageal squamous cell carcinoma(ESCC)has not been clearly elucidated.Methods:Fresh ESCC tissues were collected and grouped according to the infiltration density of CD8+T cells.After the transcriptome sequencing on these samples and the combined analyses with The Cancer Genome Atlas(TCGA)ESCC data,a secreted protein DEFB1 was selected to explore its potential role in the infiltration of CD8+T cells.Bioinformatics analyses,histological verification and in vitro experiments were then performed.Results:DEFB1 was highly expressed in ESCC,and the high expression of DEFB1 was an independent risk factor for overall survival.Since the up-regulation or down-regulation of DEFB1 did not affect the proliferation,migration and apoptosis of ESCC cells,we speculated that the oncogenic effect of DEFB1 was achieved by regulating microenvironmental characteristics.Bioinformatics analyses suggested that DEFB1 might play a major role in the inflammatory response and anti-tumor immune response,and correlate to the infiltration of immature dendritic cell(imDC)in ESCC.Histological analyses further confirmed that there were less CD8+T cells infiltrated,less CD83+mature DC(mDC)infiltrated and more CD1a+imDC infiltrated in those ESCC samples with high expression of DEFB1.After the treatment with recombinant DEFB1 protein,the maturation of DC was hindered significantly,followed by the impairment of the killing effects of T cells in both 2D and 3D culture in vitro.Conclusions:Tumor-derived DEFB1 can inhibit the maturation of DC and weaken the function of CD8+T cells,accounting for the immune tolerance in ESCC.The role of DEFB1 in ESCC deserves further exploration.

Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer

The relevant mechanism of tumor-associated macrophages(TAMs)in the treatment of colorectal cancer patients with immune checkpoint inhibitors(ICIs)is discussed,and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies.As a class of drugs widely used in clinical tumor immunotherapy,ICIs can act on regulatory molecules on cells that play an inhibitory role-immune checkpoints-and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system.The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly.The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs.ICIs can regulate the phenotypic function of TAMs,and TAMs can also affect the tolerance of colorectal cancer to ICI therapy.TAMs play an important role in ICI resistance,and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.

Repurposing drugs for solid tumor treatment:focus on immune checkpoint inhibitors

Cancer remains a significant global health challenge with limited treatment options beyond systemic therapies,such as chemotherapy,radiotherapy,and molecular targeted therapy.Immunotherapy has emerged as a promising therapeutic modality but the efficacy has plateaued,which therefore provides limited benefits to patients with cancer.Identification of more effective approaches to improve patient outcomes and extend survival are urgently needed.Drug repurposing has emerged as an attractive strategy for drug development and has recently garnered considerable interest.This review comprehensively analyses the efficacy of various repurposed drugs,such as transforming growth factor-beta(TGF-β)inhibitors,metformin,receptor activator of nuclear factor-κB ligand(RANKL)inhibitors,granulocyte macrophage colony-stimulating factor(GM-CSF),thymosinα1(Tα1),aspirin,and bisphosphonate,in tumorigenesis with a specific focus on their impact on tumor immunology and immunotherapy.Additionally,we present a concise overview of the current preclinical and clinical studies investigating the potential therapeutic synergies achieved by combining these agents with immune checkpoint inhibitors.

Identification and verification of aging-related lncRNAs for prognosis prediction and immune microenvironment in patients with head and neck squamous carcinoma

Aging is highly associated with tumor formation and progression.However,little research has explored the association of aging-related lncRNAs(ARLs)with the prognosis and tumor immune microenvironment(TIME)of head and neck squamous cell carcinoma(HNSCC).RNA sequences and clinicopathological data of HNSCC patients and normal subjects were downloaded from The Cancer Genome Atlas.In the training group,we used Pearson correlation,univariate Cox regression,least absolute shrinkage/selection operator regression analyses,and multivariate Cox regression to build a prognostic model.In the test group,we evaluated the model.Multivariate Cox regression was done to screen out independent prognostic factors,with which we constructed a nomogram.Afterward,we demonstrated the predictive value of the risk scores based on the model and the nomogram using time-dependent receiver operating characteristics.Gene set enrichment analysis,immune correlation analysis,and half-maximal inhibitory concentration were also performed to reveal the different landscapes of TIME between risk groups and to predict immuno-and chemo-therapeutic responses.The most important LINC00861 in the model was examined in HNE1,CNE1,and CNE2 nasopharyngeal carcinoma cell lines and transfected into the cell lines CNE1 and CNE2 using the LINC00861-pcDNA3.1 construct plasmid.In addition,CCK-8,Edu,and SA-β-gal staining assays were conducted to test the biofunction of LINC00861 in the CNE1 and CNE2 cells.The signature based on nine ARLs has a good predictive value in survival time,immune infiltration,immune checkpoint expression,and sensitivity to multiple drugs.LINC00861 expression in CNE2 was significantly lower than in the HNE1 and CNE1 cells,and LINC00861 overexpression significantly inhibited the proliferation and increased the senescence of nasopharyngeal carcinoma cell lines.This work built and verified a new prognostic model for HNSCC based on ARLs and mapped the immune landscape in HNSCC.LINC00861 is a protective factor for the development of HNSCC.

Prognostic significance of tumor immune microenvironment and immunotherapy:Novel insights and future perspectives in gastric cancer

Despite a decrease in gastric cancer incidence, the development of novel biologic agents and combined therapeutic strategies, the prognosis of gastric cancer remains poor. Recently, the introduction of modern immunotherapy, especially using immune checkpoint inhibitors, led to an improved prognosis in many cancers. The use of immunotherapy was also associated with manageable adverse event profiles and promising results in the treatment of patients with gastric cancer, especially in heavily pretreated patients. These data have led to an accelerated approval of some checkpoint inhibitors in this setting. Understanding the complex relationship between the host immune microenvironment and tumor and the immune escape phenomenon leading to cancer occurrence and progression will subsequently lead to the identification of prognostic immune markers. Furthermore, this understanding will result in the discovery of both new mechanisms for blocking tumor immunosuppressive signals and pathways to stimulate the local immune response by targeting and modulating different subsets of immune cells. Due to the molecular heterogeneity of gastric cancers associated with differentclinico-biologic parameters, immune markers expression and prognosis, novel immunotherapy algorithms should be personalized and addressed to selected subsets of gastric tumors, which have been proven to elicit the best clinical responses. Future perspectives in the treatment of gastric cancer include tailored dual immunotherapies or a combination of immunotherapy with other targeted agents with synergistic antitumor effects.

Multiplex imaging reveals the architecture of the tumor immune microenvironment

The tumor immune microenvironment(TME)is composed of a variety of components,such as tumor cells,immune cells,and the extracellular matrix.The TME has been studied through transcriptomic,proteomic,metabolomic,and phosphoproteomic approaches,which have provided researchers with a wealth of TME-related molecular information.

Histological differentiation impacts the tumor immune microenvironment in gastric carcinoma:Relation to the immune cycle

BACKGROUND Various histological types of gastric carcinomas(GCs)differ in terms of their pathogenesis and their preexisting background,both of which could impact the tumor immune microenvironment(TIME).However,the current understanding of the immune contexture of GC is far from complete.AIM To clarify the tumor-host immune interplay through histopathological features and the tumor immune cycle concept.METHODS In total,50 GC cases were examined(15 cases of diffuse GC,31 patients with intestinal-type GC and 4 cases of mucinous GC).The immunophenotype of GC was assessed and classified as immune desert(ID),immune excluded(IE)or inflamed(Inf)according to CD8+cell count and spatial pattern.In addition,CD68+and CD163+macrophages and programmed death-ligand 1(PD-L1)expression were estimated.RESULTS We found that GCs with different histological differentiation demonstrated distinct immune contexture.Most intestinal-type GCs had inflamed TIMEs rich in both CD8+cells and macrophages.In contrast,more aggressive diffuse-type GC more often possessed ID characteristics with few CD8+lymphocytes but abundant CD68+macrophages,while mucinous GC had an IE-TIME with a prevalence of CD68+macrophages and CD8+lymphocytes in the peritumor stroma.PD-L1 expression prevailed mostly in intestinal-type Inf-GC,with numerous CD163+cells observed.Therefore,GCs of different histological patterns have specific mechanisms of immune escape.While intestinal-type GC was more often related to PD-L1 expression,diffuse and mucinous GCs possessing more aggressive behavior demonstrated low immunogenicity and a lack of tumor antigen recognition or immune cell recruitment into the tumor clusters.CONCLUSION These data help to clarify the links between tumor histogenesis and immunogenicity for a better understanding of GC biology and more tailored patient management.

Prognostic tumor microenvironment gene and the relationship with immune infiltration characteristics in metastatic breast cancer

The aim of this study was to reveal genes associated with breast cancer metastasis,to investigate their intrinsic relationship with immune cell infiltration in the tumor microenvironment,and to screen for prognostic biomarkers.Gene expression data of breast cancer patients and their metastases were downloaded from the GEO,TCGA database.R language package was used to screen for differentially expressed genes,enrichment analysis of genes,PPI network construction,and also to elucidate key genes for diagnostic and prognostic survival.Spearman’s r correlation was used to analyze the correlation between key genes and infiltrating immune cells.We screened 25 hub genes,FN1,CLEC5A,ATP8B4,TLR7,LY86,PTGER3 and other genes were differentially expressed in cancer and paraneoplastic tissues.However,patients with higher expression of CD1C,IL-18 breast cancer had a better prognosis in the 10 years survival period,while patients with high expression of FN1,EIF4EBP1 tumors had a worse prognosis.In addition,TP53 and HIF1 genes are closely related to the signaling pathway of breast cancer metastasis.In this study,gene expression of ATP8B4 and CD1C were correlated with cancer tissue infiltration of CD8^(+)T lymphocytes,while GSE43816,GSE62327 and TCGA databases showed that CD8^(+)T lymphocytes were closely associated with breast cancer progression.Functional enrichment analysis of genes based on expression differences yielded key genes of prognostic value in the breast cancer microenvironment.

Development and validation of a tumor microenvironment-related prognostic signature in lung adenocarcinoma and immune infiltration analysis

Objective Tumor-infiltrating immune cells and stromal cells in the tumor microenvironment(TME)significantly affect the prognosis of and immune response to lung adenocarcinoma(LUAD).In this study,we aimed to develop a novel TME-related prognostic model based on immune and stromal genes in LUAD.Methods LUAD data from the TCGA database were used as the training cohort,and three Gene Expression Omnibus(GEO)datasets were used as the testing cohort.The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data algorithm was used to analyze the immune and stromal genes involved in the TME.Kaplan-Meier and Cox regression analyses were used to identify prognostic genes and construct a TME-related prognostic model.Gene set enrichment analysis and TIMER were used to analyze the immune features and signaling pathways of the model.Results A TME-related prognostic model based on six hub genes was generated that significantly stratified patients into the high-and low-risk groups in terms of overall survival.The model had strong predictive ability in both the training(TCGA)and testing(GEO)datasets and could serve as an independent prognostic factor for LUAD.Moreover,the low-risk group was characterized by greater immune cell infiltration and antitumor immune activity than the high-risk group.Importantly,the signature was closely associated with immune checkpoint molecules,which may serve as a predictor of patient response to immunotherapy.Finally,the hub genes BTK,CD28,INHA,PIK3CG,TLR4,and VEGFD were considered novel prognostic biomarkers for LUAD and were significantly correlated with immune cells.Conclusion The TME-related prognostic model could effectively predict the prognosis and reflect the TME status of LUAD.These six hub genes provided novel insights into the development of new therapeutic strategies.