Tumor Microenvironment in Adrenocortical Carcinoma: Barrier to Immunotherapy Success?
Ontology highlight
ABSTRACT:
SUBMITTER: Georgantzoglou N
PROVIDER: S-EPMC8069982 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Increasing evidence confirms that tumor microenvironment (TME) can influence tumor progression and treatment, but TME is still understudied in adrenocortical carcinoma (ACC). In this study, we first scored TME using the xCell algorithm, then defined genes associated with TME, and then used consensus unsupervised clustering analysis to construct TME-related subtypes. Meanwhile, weighted gene co-expression network analysis was used to identify modules correlated with TME-related subtypes. Ultimately, the LASSO-Cox approach was used to establish a TME-related signature. The results showed that TME-related scores in ACC may not correlate with clinical features but do promote a better overall survival. Patients were classified into two TME-related subtypes. Subtype 2 had more immune signaling features, higher expression of immune checkpoints and MHC molecules, no CTNNB1 mutations, higher infiltration of macrophages and endothelial cells, lower tumor immune dysfunction and exclusion scores, and higher immunophenoscore, suggesting that subtype 2 may be more sensitive to immunotherapy. 231 modular genes highly relevant to TME-related subtypes were identified, and a 7-gene TME-related signature that independently predicted patient prognosis was established. Our study revealed an integrated role of TME in ACC and helped to identify those patients who really responded to immunotherapy, while providing new strategies on risk management and prognosis prediction.
| S-EPMC10000893 | biostudies-literature
Project description:Adrenocortical carcinoma (ACC) is a rare malignancy with dismal prognosis. Hypoxia is one of characteristics of cancer leading to tumor progression. For ACC, however, no reliable prognostic signature on the basis of hypoxia genes has been built. Our study aimed to develop a hypoxia-associated gene signature in ACC. Data of ACC patients were obtained from TCGA and GEO databases. The genes included in hypoxia risk signature were identified using the Cox regression analysis as well as LASSO regression analysis. GSEA was applied to discover the enriched gene sets. To detect a possible connection between the gene signature and immune cells, the CIBERSORT technique was applied. In ACC, the hypoxia signature including three genes (CCNA2, COL5A1, and EFNA3) was built to predict prognosis and reflect the immune microenvironment. Patients with high-risk scores tended to have a poor prognosis. According to the multivariate regression analysis, the hypoxia signature could be served as an independent indicator in ACC patients. GSEA demonstrated that gene sets linked to cancer proliferation and cell cycle were differentially enriched in high-risk classes. Additionally, we found that PDL1 and CTLA4 expression were significantly lower in the high-risk group than in the low-risk group, and resting NK cells displayed a significant increase in the high-risk group. In summary, the hypoxia risk signature created in our study might predict prognosis and evaluate the tumor immune microenvironment for ACC.
| S-EPMC8481041 | biostudies-literature
Project description:Background: Adrenocortical carcinoma (ACC) is a rare malignant endocrine tumor derived from the adrenal cortex. Because of its highly aggressive nature, the prognosis of patients with adrenocortical carcinoma is not impressive. Hypoxia exists in the vast majority of solid tumors and contributes to invasion, metastasis, and drug resistance. This study aimed to reveal the role of hypoxia in Adrenocortical carcinoma and develop a hypoxia risk score (HRS) for Adrenocortical carcinoma prognostic prediction. Methods: Hypoxia-related genes were obtained from the Molecular Signatures Database. The training cohorts of patients with adrenocortical carcinoma were downloaded from The Cancer Genome Atlas, while another three validation cohorts with comprehensive survival data were collected from the Gene Expression Omnibus. In addition, we constructed a hypoxia classifier using a random survival forest model. Moreover, we explored the relationship between the hypoxia risk score and immunophenotype in adrenocortical carcinoma to evaluate the efficacy of immune check inhibitors (ICI) therapy and prognosis of patients. Results: HRS and tumor stage were identified as independent prognostic factors. HRS was negatively correlated with immune cycle activity, immune cell infiltration, and the T cell inflammatory score. Therefore, we considered the low hypoxia risk score group as the inflammatory immunophenotype, whereas the high HRS group was a non-inflammatory immunophenotype. In addition, the HRS was negatively related to the expression of common immune checkpoint molecules such as PD-L1, CD200, CTLA-4, and TIGIT, suggesting that patients with a lower hypoxia risk score respond better to immunotherapy. Conclusion: We developed and validated a novel hypoxia risk score to predict the immunophenotype and response of patients with adrenocortical carcinoma to immune check inhibitors therapy. These findings not only provide fresh prognostic indicators for adrenocortical carcinoma but also offer several promising treatment targets for this disease.
| S-EPMC9792869 | biostudies-literature
Project description:Adrenocortical carcinoma (ACC) is a rare, highly aggressive cancer, often insensitive to conventional chemotherapeutics agents. Early diagnosis, followed by radical surgical resection plus/minus adjuvant mitotane therapy, is nowadays the only valuable option. Unfortunately, one out of four patients has metastatic disease at diagnosis and most of radically resected ACC patients are destined to recur with local or metastatic disease. Numerous efforts aimed at identifying molecular alterations crucial for ACC pathogenesis have been extensively conducted, with the hope to develop new treatments. Indeed, multiple genes and pathways have been identified as potentially targetable in ACC patients; however, despite the strong preclinical rationale, translational findings to clinical trials led to date to disappointing results. The immunotherapeutic intervention targeting T-cell checkpoint molecules has been proposed as well, but results obtained in early studies indicate that ACC patients would be unlikely to benefit from immunotherapy. Genetic alterations of different pathways involved in ACC carcinogenesis are also known substrates of resistance to immunotherapy. Among them, β-catenin gene CTNNB1 and TP53 gene are frequently mutated in ACC samples. Overactivation of the β-catenin pathway and loss of p53 protein function are potential tumor-intrinsic factors that, impacting on the ability of ACC cells to recruit dendritic cells, leading to T-cell exclusion, put this tumor among those that are potentially resistant to immunotherapy. Moreover, the steroid phenotype, which implies glucocorticoids hypersecretion in a subset of ACC, contributes to generating an immunosuppressive microenvironment. Here, we review clinical results of immunotherapy in ACC and we highlight molecular mechanisms driving immunotherapy failure in ACC, suggesting possible approaches to overcome resistance.
| S-EPMC6463568 | biostudies-literature
Project description:BackgroundCD74 is ectopically expressed in many tumors and can regulate tumor immunity. However, there are many gaps in the study of the prognostic value of CD74 expression and immune infiltration in hepatocellular carcinoma (HCC).MethodsAn online tumor database was searched to obtain data on gene/protein expression. Immune infiltration analysis was performed using the Tumor Immune Estimation Resource and Comprehensive Analysis on Multi-Omics of Immunotherapy in Pan-cancer databases. Single-cell data were obtained from the Tissue-specific Gene Expression and Regulation, Single-cell Transcriptomes of Tumor Immune Microenvironment and Tumor Immune Single-cell Hub 2 databases.ResultsCD74 was highly expressed in HCC patients. HCC patients with high CD74 expression who consumed alcohol or were negative for hepatitis virus had a better prognosis than patients with low CD74 expression. CD74 was mainly enriched in immune response regulation pathways. Both copy number variations in CD74 and CD74 expression patterns affected the infiltration levels of immune cells. Interestingly, CD74 regulated the differentiation of myeloid cells. CD74 in macrophages and dendritic cells (DCs) forms complex networks with malignant cells and hepatic progenitor cell (HPC)-like cells, respectively. High CD74 expression in HPC-like cells and malignant cells significantly decreased the fraction of C-type lectin domain family 9 A (CLEC9A)-cDC1+ DCs and IL-1B+ macrophages, respectively. Their crosstalk subsequently shaped the tumor microenvironment of HCC, possibly through the CD74-MIF axis. Importantly, patients with high CD74 expression presented higher immune scores and achieved good outcomes after receiving immunotherapy.ConclusionHigh CD74 expression is associated with the abundance of a variety of immune cell types, mediating interactions among tumor and immune cells and shaping the malignant behavior of HCC. In summary, CD74 may be a hallmark for determining the prognosis and immune cell infiltration levels of HCC patients.
| S-EPMC11308498 | biostudies-literature
Project description:Adrenocortical carcinoma (ACC) is a rare epithelial neoplasm, with a high tendency for local invasion and distant metastases, with limited treatment options. Surgical treatment is the method of choice. For decades, the mainstay of pharmacological treatment has been the adrenolytic drug mitotane, in combination with chemotherapy. Immunotherapy is the latest revolution in cancer therapy, however preliminary data with single immune checkpoint inhibitors showed a modest activity in ACC patients. The anti-neoplastic activity of immune checkpoint inhibitors such as anti-cytotoxic-T-lymphocyte-associated-antigen 4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), and anti-PD-ligand-1 (PD-L1) antibodies in different solid tumors has aroused interest to explore the potential therapeutic effect in ACC as well. Multiple ongoing clinical trials are currently evaluating the role of immune checkpoint inhibitors in ACC (pembrolizumab, combination pembrolizumab and relacorilant, nivolumab, combination nivolumab and ipilimumab). The primary and acquired resistance to immunotherapy continue to counter treatment efficacy. Therefore, attempts are made to combine therapy: anti-PD-1 antibody and anti-CTLA-4 antibody, anti-PD-1 antibody and antagonist of the glucocorticoid receptor. The inhibitors of immune checkpoints would benefit patients with antitumor immunity activated by radiotherapy. Immunotherapy is well tolerated by patients; the most frequently observed side effects are mild. The most common adverse effects of immunotherapy are skin and gastrointestinal disorders. The most common endocrinopathy during anti-CTLA treatment is pituitary inflammation and thyroid disorders.
| S-EPMC7909536 | biostudies-literature
Project description:Tumor immune microenvironment (TIME) include tumor cells, immune cells, cytokines, etc. The interactions between these components, which are divided into anti-tumor and pro-tumor, determine the trend of anti-tumor immunity. Although the immune system can eliminate tumor through the cancer-immune cycle, tumors appear to eventually evade from immune surveillance by shaping an immunosuppressive microenvironment. Immunotherapy reshapes the TIME and restores the tumor killing ability of anti-tumor immune cells. Herein, we review the function of immune cells within the TIME and discuss the contribution of current mainstream immunotherapeutic approaches to remolding the TIME. Changes in the immune microenvironment in different forms under the intervention of immunotherapy can shed light on better combination treatment strategies.
| S-EPMC9299092 | biostudies-literature
Project description:Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a high rate of mortality and recurrence. N6-methyladenosine methylation (m6A) is the most common modification to affect cancer development, but to date, the potential role of m6A regulators in ACC prognosis is not well understood. In this study, we systematically analyzed 21 m6A regulators in ACC samples from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. We identified three m6A modification patterns with different clinical outcomes and discovered a significant relationship between diverse m6A clusters and the tumor immune microenvironment (immune cell types and ESTIMATE algorithm). Additionally, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) revealed that the m6A clusters were strongly associated with immune infiltration in the ACC. Next, to further explore the m6A prognostic signatures in ACC, we implemented Lasso (Least Absolute Shrinkage and Selection Operator) Cox regression to establish an eight-m6A-regulator prognostic model in the TCGA dataset, and the results showed that the model-based high-risk group was closely correlated with poor overall survival (OS) compared with the low-risk group. Subsequently, we validated the key modifications in the GEO datasets and found that high HNRNPA2B1 expression resulted in poor OS and event-free survival (EFS) in ACC. Moreover, to further decipher the molecular mechanisms, we constructed a competing endogenous RNA (ceRNA) network based on HNRNPA2B1, which consists of 12 long noncoding RNAs (lncRNAs) and 1 microRNA (miRNA). In conclusion, our findings indicate the potential role of m6A modification in ACC, providing novel insights into ACC prognosis and guiding effective immunotherapy.
| S-EPMC7966528 | biostudies-literature
Project description:BackgroundTo identify prognostic genes which were associated with adrenocortical carcinoma (ACC) tumor microenvironment (TME).Methods and materialsTranscriptome profiles and clinical data of ACC samples were collected from The Cancer Genome Atlas (TCGA) database. We use ESTIMATE (estimation of stromal and Immune cells in malignant tumor tissues using expression data) algorithm to calculate immune scores, stromal scores and estimate scores. Heatmap and volcano plots were applied for differential analysis. Venn plots were used for intersect genes selection. We used protein-protein interaction (PPI) networks and functional analysis to explore underlying pathways. After performing stepwise regression method and multivariate Cox analysis, we finally screened hub genes associated with ACC TME. We calculated risk scores (RS) for ACC cases based on multivariate Cox results and evaluated the prognostic value of RS shown by receiver operating characteristic curve (ROC). We investigated the association between hub genes with immune infiltrates supported by algorithm from online TIMER database.ResultsGene expression profiles and clinical data were downloaded from TCGA. Lower immune scores were observed in disease with distant metastasis (DM) and locoregional recurrence (LR) than other cases (P = .0204). Kaplan-Meier analysis revealed that lower immune scores were significantly associated with poor overall survival (OS) (P = .0495). We screened 1649 differentially expressed genes (DEGs) and 1521 DEGs based on immune scores and stromal scores, respectively. Venn plots helped us find 1122 intersect genes. After analysing by cytoHubba from Cytoscape software, 18 hub genes were found. We calculated RS and ROC showed significantly predictive accuracy (area under curve (AUC) = 0.887). ACC patients with higher RS had worse survival outcomes (P < .0001). Results from TIMER (tumor immune estimation resource) database revealed that HLA-DOA was significantly related with immune cells infiltration.ConclusionWe screened a list of TME-related genes which predict poor survival outcomes in ACC patients from TCGA database.
| S-EPMC6997077 | biostudies-literature
Project description:Intralesional therapy with oncolytic viruses (OVs) leads to the activation of local and systemic immune pathways, which may present targets for further combinatorial therapies. Here, we used human tumor histocultures as well as syngeneic tumor models treated with Newcastle disease virus (NDV) to identify a range of immune targets upregulated with OV treatment. Despite tumor infiltration of effector T lymphocytes in response to NDV, there was ongoing inhibition through programmed death ligand 1 (PD-L1), acting as a mechanism of early and late adaptive immune resistance to the type I IFN response and T cell infiltration, respectively. Systemic therapeutic targeting of programmed cell death receptor 1 (PD-1) or PD-L1 in combination with intratumoral NDV resulted in the rejection of both treated and distant tumors. These findings have implications for the timing of PD-1/PD-L1 blockade in conjunction with OV therapy and highlight the importance of understanding the adaptive mechanisms of immune resistance to specific OVs for the rational design of combinatorial approaches using these agents.
| S-EPMC5873884 | biostudies-other