Increased apoptosis is associated with robust immune cell infiltration and cytolytic activity in breast cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Murthy V
PROVIDER: S-EPMC8332871 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The somatic co-evolution of tumors and the cellular immune responses that combat them drives the diversity of immune-tumor interactions. This includes tumor mutations that generate neo-antigenic epitopes that elicit cytotoxic T-cell activity and subsequent pressure to select for genetic loss of antigen presentation. Most studies have focused on how tumor missense mutations can drive tumor immunity, but frameshift mutations have the potential to create far greater antigenic diversity. However, expression of this antigenic diversity is potentially regulated by Nonsense Mediated Decay (NMD) and NMD has been shown to be of variable efficiency in cancers. Here we studied how mutational changes influence global NMD and cytolytic immune responses. Using TCGA datasets, we derived novel patient-level metrics of 'NMD burden' and interrogated how different mutation and most importantly NMD burdens influence cytolytic activity using machine learning models and survival outcomes. We find that NMD is a significant and independent predictor of immune cytolytic activity. Different indications exhibited varying dependence on NMD and mutation burden features. We also observed significant co-alteration of genes in the NMD pathway, with a global increase in NMD efficiency in patients with NMD co-alterations. Finally, NMD burden also stratified patient survival in multivariate regression models in subset of cancer types. Our work suggests that beyond selecting for mutations that elicit NMD in tumor suppressors, tumor evolution may react to the selective pressure generated by inflammation to globally enhance NMD through coordinated amplification and/or mutation.
| S-EPMC6837539 | biostudies-literature
Project description:ObjectiveAs a pseudokinase, Tribbles Pseudokinase 3 (TRIB3) is implicated in a wide array of biological processes, including cell signal transduction, metabolic regulation, stress responses, and immune regulation. While its significant role in the immune regulation of certain cancers is well-established, the specific functions and impact of TRIB3 in head and neck squamous cell carcinoma (HNSC) remain unclear.MethodsThe data of RNA-sequence was acquired from the TCGA database to analyze the expression patterns of TRIB3 and elucidate its prognostic value in HNSC patients. Furthermore, the correlation between TRIB3 and tumor mutation burden, clinical data, immune checkpoint genes, and immune cell infiltration was explored. Moreover, the TRIB3 location in tumor tissues and subcellular structures was identified via Tisch in the HPA database, and the potential protein interaction molecules for TRIB3 were elucidated in the STRING database. The potential TRIB3 gene function was assessed using gene set enrichment analysis (GSEA), whereas the TRIB3 expression levels in clinical HNSC samples were verified by RT-qPCR and immunohistochemistry. the role of TRIB3 in enhancing the malignant behavior of HNSC cells was validated in vitro through a series of methods including RT-qPCR, CCK8 assay, wound healing assay, and transwell assay.ResultsIt was revealed that TRIB3 was significantly overexpressed in the nucleus and cytoplasm of HNSC. Furthermore, this overexpression markedly enhanced the migration ability of tumor cells. As an independent prognostic factor, TRIB3 was associated with advanced tumor T stage and was significantly involved with tumor mutation burden and immune cell infiltration in HNSC. Moreover, it was observed that TRIB3 was not a predicted factor for PD1/PDL1 and ATL4 inhibitor treatment; however, it was substantially correlated with various immune evasion-related genes in HNSC.ConclusionTRIB3 could serve as a potential prognostic marker for HNSC and might be a key gene mediating HNSC immune evasion.
| S-EPMC10791810 | biostudies-literature
Project description:Background: Immunotherapy provided unprecedented advances in the treatment of several previously untreated cancers. However, these immunomodulatory maneuvers showed limited response to patients with glioma in clinical trials. Our aim was to depict the immune characteristics of glioma with immune cytolytic activity at genetic and transcriptome levels. Methods: In total, 325 gliomas from CGGA dataset as training cohort and 699 gliomas from TCGA dataset as validation cohort were enrolled in our analysis. We calculated the immune cytolytic activity for 1,000 of gliomas. The characteristics of immune cytolytic activity in gliomas were interpreted by the corresponding clinical, molecular genetics and radiological information. Results: We found that immune cytolytic activity was highly associated with molecular, clinical, and edema extent. High cytolytic activity gliomas were more likely to be diagnosed as glioblastoma and might be a potential marker of mesenchymal subtype. Moreover, those gliomas exhibited significantly increased copy number alterations including recurrent focal amplifications of PDGFA and EGFR, as well as recurrent deletions of CDKN2A/B. Subsequent biological function analysis revealed that the immune response and immune checkpoints expression were significantly correlated with the cytolytic activity of gliomas. Immune cytolytic activity was significantly positively associated with the extent of peri-tumor edema and was independently correlated with reduced survival time. Conclusion: Our results highlighted the immunoregulatory mechanism heterogeneity of gliomas. Cytolytic activity, indirectly reflected by the extent of peri-tumor edema, may provide a potential index to evaluate the status of immune microenvironment and immune checkpoints in glioma, which should be fully valued for precision classification and immunotherapy.
| S-EPMC6688525 | biostudies-literature
Project description:How the genomic landscape of a tumor shapes and is shaped by anti-tumor immunity has not been systematically explored. Using large-scale genomic data sets of solid tissue tumor biopsies, we quantified the cytolytic activity of the local immune infiltrate and identified associated properties across 18 tumor types. The number of predicted MHC Class I-associated neoantigens was correlated with cytolytic activity and was lower than expected in colorectal and other tumors, suggesting immune-mediated elimination. We identified recurrently mutated genes that showed positive association with cytolytic activity, including beta-2-microglobulin (B2M), HLA-A, -B and -C and Caspase 8 (CASP8), highlighting loss of antigen presentation and blockade of extrinsic apoptosis as key strategies of resistance to cytolytic activity. Genetic amplifications were also associated with high cytolytic activity, including immunosuppressive factors such as PDL1/2 and ALOX12B/15B. Our genetic findings thus provide evidence for immunoediting in tumors and uncover mechanisms of tumor-intrinsic resistance to cytolytic activity.
| S-EPMC4856474 | biostudies-literature
Project description:BackgroundHigh temperature requirement A1 (HTRA1), a member of the HTRA family, is a serine peptidase involved in many crucial bioprocesses such as proliferation, mitochondrial homeostasis, apoptosis, and protein quality control. It also plays an important role in the development of various tumors. However, the potential role and mechanisms of action of HTRA1 in breast cancer (BRCA) remain unclear. We conducted a bioinformatics-based study to investigate HTRA1 expression in BRCA alongside its associations with immune-cell infiltrates and survival outcomes.MethodsThe expression of HTRA1 in BRCA samples was analyzed using RNAseq datasets from The Cancer Genome Atlas and Gene Expression Omnibus. R software was employed to assess the relationship between HTRA1 expression and clinicopathological characteristics, tumor-infiltrating immune cells, and immunity-associated biomarkers in BRCA. MethSurv and cBioPortal database were utilized to evaluate DNA methylation and genovariation within the HTRA1 DNA. Receiver operating characteristic curves, Kaplan-Meier analysis, and Cox regression were performed to estimate the impact of HTRA1 on diagnosis, prognosis, and response to chemotherapy in BRCA.ResultsHTRA1 expression was significantly downregulated in BRCA tissues compared to adjacent normal breast tissue controls. Differentially expressed genes associated with HTRA1 expression primarily enriched in cell proliferation pathways. Furthermore, altered HTRA1 expression significantly correlated with patient age, tumor histological type, T stage, progesterone receptor/estrogen receptor status, and PAM50 subtype of BRCA. Both positive and negative associations were observed between HTRA1 levels and the abundance of different types of immune cells, as well as immune biomarkers, including resting mast cells, follicular helper T cells, PD-L1, p53, and Ki67. Low HTRA1 expression was related with pathological complete response in luminal B BRCA patients undergoing chemotherapy. Additionally, lower HTRA1 expression in BRCA was associated with inferior overall survival and relapse-free survival.ConclusionsHTRA1 expression is associated with immune-cell infiltration, response to chemotherapy, and survival outcomes in BRCA. HTRA1 has the potential to serve as a promising biomarker and therapeutic target moving forward.
| S-EPMC10774071 | biostudies-literature
Project description:BackgroundThe kinesin-13 family member 2C (KIF2C) is a versatile protein participating in many biological processes. KIF2C is frequently up-regulated in multiple types of cancer and is associated with cancer development. However, the role of KIF2C in immune cell infiltration of tumor microenvironment and immunotherapy in breast cancer remains unclear.MethodsThe expression of KIF2C was analyzed using Tumor Immune Estimation Resource (TIMER) database and further verified by immunohistochemical staining in human breast cancer tissues. The correlation between KIF2C expression and clinical parameters, the impact of KIF2C on clinical prognosis and independent prognostic factors were analyzed by using TCGA database, the Kaplan-Meier plotter, and Univariate and multivariate Cox analyses, respectively. The nomograms were constructed according to independent prognostic factors and validated with C-index, calibration curves, ROC curves, and decision curve analysis. A gene set enrichment analysis (GSEA) was performed to explore the underlying molecular mechanisms of KIF2C. The degree of immune infiltration was assessed by the Estimation of Stromal and Immune cells in Malignant Tumor tissues using the Expression (ESTIMATE) algorithm and the single sample GSEA (ssGSEA). The Tumor mutational burden and Tumor Immune Dysfunction and Rejection (TIDE) were used to analyze immunotherapeutic efficiency. Finally, the KIF2C-related competing endogenous RNA (ceRNA) network was constructed to predict the putative regulatory mechanisms of KIF2C.ResultsKIF2C was remarkably up-regulated in 18 different types of cancers, including breast cancer. Kaplan-Meier survival analysis showed that high KIF2C expression was associated with poor overall survival (OS). KIF2C expression was associated with clinical parameters such as age, TMN stage, T status, and molecular subtypes. We identified age, stage, estrogen receptor (ER) and KIF2C expression as OS-related independent prognosis factors for breast cancer. An OS-related nomogram was developed based on these independent prognosis factors and displayed good predicting ability for OS of breast cancer patients. Finally, our results revealed that KIF2C was significantly related to immune cell infiltration, tumor mutational burden, and immunotherapy in patients with breast cancer.ConclusionKIF2C was overexpressed in breast cancer and was positively correlated with immune cell infiltration and immunotherapy response. Therefore, KIF2C can serve as a potential biomarker for prognosis and immunotherapy in breast cancer.
| S-EPMC10071625 | biostudies-literature
Project description:Background: This study aimed to explore the prognostic value of angiogenesis-related genes (ARGs) and their association with immune cell infiltration (ICI) in breast cancer (BC). Methods: Transcriptome data of BC were obtained from the TCGA and GEO databases. Differentially expressed ARGs were identified by the limma package. The identification of key genes and construction of the risk score model were performed by univariate and multivariate Cox regression algorithms. The prognostic value of the risk score was assessed by ROC curves and nomogram. GO, KEGG pathway, and GSEA were used to investigate the biological functions of differentially expressed genes (DEGs), and CIBERSORT, ssGSEA, and xCell algorithms were performed to estimate the ICI in high-risk and low-risk groups. The correlations between prognostic biomarkers and differentially distributed immune cells were assessed. Moreover, a ceRNA regulatory network based on prognostic biomarkers was constructed and visualized by Cytoscape software. Results: A total of 18 differentially expressed ARGs were identified between tumor and adjacent normal tissue samples. TNFSF12, SCG2, COL4A3, and TNNI3 were identified as key prognostic genes by univariate and multivariate Cox regression analyses. The risk score model was further constructed based on the four-gene signature and validated in GSE7390 and GSE88770 datasets. ROC curves and nomogram indicated that the risk score had good accuracy for determining BC patient survival. Biological function analysis showed that DEGs in high- and low-risk groups had a high enrichment in immune-related biological processes and signaling pathways. Moreover, significantly different ICIs were found between high- and low-risk groups, such as memory B cells, CD8+ T cells, resting memory CD4+ T cells, follicular helper T cells, regulatory T cells, monocytes, M2 macrophages, and neutrophils, and each prognostic biomarker was significantly correlated with one or more immune cell types. Conclusion: The current study identified novel prognostic ARGs and developed a prognostic model for predicting survival in patients with BC. Furthermore, this study indicated that ICI may act as a bond between angiogenesis and BC. These findings enhance our understanding of angiogenesis in BC and provide novel guidance on developing therapeutic targets for BC patients.
| S-EPMC9121305 | biostudies-literature
Project description:Evaluation of the functional aspects if the tumor immune microenvironment (TIME), such as the recently introduced cytolytic activity score (CYT) index have been under the spotlight in cancer research; however, clinical relevance of immune cell killing activity in breast cancer has never been analyzed in large patient cohorts. We hypothesized that CYT reflects the immune activity of TIME and can predict patient survival. A total of 7533 breast cancer patients were analyzed as both discovery and validation cohorts. We found that high CYT was associated with advanced histological grade and triple-negative breast cancer (TNBC). High CYT in tumors was significantly associated with better survival in TNBC, but unexpectedly, not in other breast cancer subtypes. High CYT TNBC included both favorable immune-related, as well as unfavorable (suppressive) inflammation-related gene sets, and characterized by high infiltration with T cells and B cells. High CYT TNBC was associated with high homologous recombination deficiency and low somatic copy number alteration score and less mutant allele tumor heterogeneity, but not with tumor mutation burden (TMB). Although CYT was not associated with pathological complete response after neoadjuvant chemotherapy, it was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, CYT of TNBC is associated with enhanced anti-cancer immunity, less intra-tumoral heterogeneity, and with better survival.
| S-EPMC8332854 | biostudies-literature
Project description:BackgroundIncreasing evdence supports the suggestion that the immune cell infiltration (ICI) patterns play a pivotal role in tumor progression in breast cancer (BRCA). Nonetheless, there has been no comprehensive analysis of the ICI patterns effects on the clinical outcomes and immunotherapy.MethodsMultiomic data for BRCA samples were downloaded from TCGA. ESTIMATE algorithm, ssGSEA method, and CIBERSORT analysis were used to uncover the landscape of the tumor immune microenvironment (TIME). BRCA subtypes based on the ICI pattern were identified by consensus clustering and principal-component analysis was performed to obtain the ICI scores to quantify the ICI patterns in individual tumors. Their prognostic value was validated by the Kaplan-Meier survival curves. Gene set enrichment analysis (GSEA) was applied for functional annotation. Immunophenoscore (IPS) was employed to explore the immunotherapeutic role of the ICI scores. Finally, the mutation data was analyzed by using the "maftools" R package.ResultsThree different immune infiltration patterns with a distinct prognosis and biological signature were recognized among 1,198 BRCA samples. The characteristics of TIME under these three patterns were highly consistent with three known immune profiles: immune- excluded, immune-desert, and immune-inflamed phenotypes, respectively. The identification of the ICI patterns within individual tumors based on the ICI score, developed under the ICI-related signature genes, contributed into dissecting biological processes, clinical outcome, immune cells infiltration, immunotherapeutic effect, and genetic variation. High ICI score subtype, characterized with a suppression of immunity, suggested an immune-exhausted phenotype. Abundant effective immune cells were discovered in the low ICI score patients, which corresponded to an immune-activated phenotype and might present an immunotherapeutic advantage. Immunophenoscore was implemented as a surrogate of immunotherapeutic outcome, low-ICI scores samples obtained a significantly higher immunophenoscore. Enrichment of the JAK/STAT and VEGF signal pathways were activated in the ICI low-score subgroup. Finally, the synergistic effect between the ICI score and the tumor mutation burden (TMB) was confirmed.ConclusionThis work comprehensively elucidated that the ICI patterns served as an indispensable player in complexity and diversity of TIME. Quantitative identification of the ICI patterns in individual tumor will contribute into mapping the landscape of TIME further optimizing precision immunotherapy.
| S-EPMC8429934 | biostudies-literature
Project description:BackgroundFerroptosis, a recently discovered form of cell death, whose role in basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) has not been well disclosed. To improve our understanding of the differences in tumor progression and therapeutic effects between BCC and SCC, and to find potential therapeutic targets, this study systematically analyzed ferroptosis-related genes (FRGs) and their associated local immune cytolytic activity (LICA) and tumor microenvironment (TME) metabolic function differences.MethodsTwo bulk RNA-seq datasets, GSE7553 and GSE125285, from the Gene Expression Omnibus database were compared within and between groups to screen for common differentially expressed genes (DEGs) for enrichment analysis. The currently recognized FRGs in DEGs gene set were selected as the targets to analyze their correlation and difference in LICA and TME metabolic functions. And validated using immune cell populations from another single-cell RNA-seq (scRNA-seq) dataset (GSE123813) to accurately understand the difference in LICA. All of the gene sets for functional enrichment analysis comes from published results and MSigDB database.ResultsTen FRGs were used to further analyze the differences in LICA and TME metabolic functions between BCC and SCC. In the SCC samples, LICA (e.g. Treg, CCR, Cytolytic activity, etc.) and TME metabolic functions (e.g. lipid and energy, etc.) were significantly related to ferroptosis genes (e.g. SLC1A5, CD44, NQO1, HMOX1 and STEAP3), and the ferroptosis potential index were also significantly higher than that in the BCC samples. Finally, based on these ten FRGs and related enrichment results, we postulated a model of NQO1 homeostasis regulated by FRGs during induction of ferroptosis in SCC.ConclusionsThe results showed that three FRGs, SLC1A5, CD44 and NQO1, have significant potential in targeted therapies for SCC chemotherapy resistance. And two FRGs, STEAP3 and HMOX1, formed a synergistic effect on the occurrence of ferroptosis in tumor cells. Our findings can be used as the main research materials for metastasis and chemotherapy resistance in SCC patients.
| S-EPMC9134950 | biostudies-literature