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Unraveling tumour microenvironment heterogeneity in nasopharyngeal carcinoma identifies biologically distinct immune subtypes predicting prognosis and immunotherapy responses.

ABSTRACT: Currently, there is no strong evidence of the well-established biomarkers for immune checkpoint inhibitors (ICIs) in nasopharyngeal carcinoma (NPC). Here, we aimed to reveal the heterogeneity of tumour microenvironment (TME) through virtual microdissection of gene expression profiles. An immune-enriched subtype was identified in 38% (43/113) of patients, which was characterized by significant enrichment of immune cells or immune responses. The remaining patients were therefore classified as a non-Immune Subtype (non-IS), which exhibited highly proliferative features. Then we identified a tumour immune evasion state within the immune-enriched subtype (18/43, 42%), in which high expression of exclusion- and dysfunction-related signatures was observed. These subgroups were designated the Evaded and Active Immune Subtype (E-IS and A-IS), respectively. We further demonstrated that A-IS predicted favourable survival and improved ICI response as compared to E-IS and non-IS. In summary, this study introduces the novel immune subtypes and demonstrates their feasibility in tailoring immunotherapeutic strategies.

SUBMITTER: Chen YP

PROVIDER: S-EPMC7798236 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Unraveling tumour microenvironment heterogeneity in nasopharyngeal carcinoma identifies biologically distinct immune subtypes predicting prognosis and immunotherapy responses.

Chen Yu-Pei YP Lv Jia-Wei JW Mao Yan-Ping YP Li Xiao-Min XM Li Jun-Yan JY Wang Ya-Qin YQ Xu Cheng C Li Ying-Qin YQ He Qing-Mei QM Yang Xiao-Jing XJ Lei Yuan Y Shen Jia-Yi JY Tang Ling-Long LL Chen Lei L Zhou Guan-Qun GQ Li Wen-Fei WF Du Xiao-Jing XJ Guo Rui R Liu Xu X Zhang Yuan Y Zeng Jing J Yun Jing-Ping JP Sun Ying Y Liu Na N Ma Jun J

Molecular cancer 20210111 1

Currently, there is no strong evidence of the well-established biomarkers for immune checkpoint inhibitors (ICIs) in nasopharyngeal carcinoma (NPC). Here, we aimed to reveal the heterogeneity of tumour microenvironment (TME) through virtual microdissection of gene expression profiles. An immune-enriched subtype was identified in 38% (43/113) of patients, which was characterized by significant enrichment of immune cells or immune responses. The remaining patients were therefore classified as a no ...[more]

PMID: 33430876

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Project description:BackgroundNeuroblastoma (NB) is a childhood cancer originating from immature nerve cells in the sympathetic nervous system. Current clinical and molecular subtyping methods for NB have limitations in providing accurate prognostic information and guiding treatment decisions.ResultsTo overcome these challenges, we explored the microenvironment of NB based on the knowledge-based functional gene expression signatures (Fges), which revealed heterogeneous subtypes. Consensus clustering of Fges activity scores identified three subtypes (Cluster 1, Cluster 2, and Cluster 3) that demonstrated significant differences in prognosis compared to mainstream subtypes. We assessed the immune infiltration, immunogenicity, CD8T cytotoxicity, and tumor purity of these subtypes, uncovering their distinct biological functions. Cluster 1 and Cluster 2 exhibited higher immunoreactivity, while Cluster 3 displayed higher tumor purity and poor prognosis. Gene ontology annotation and pathway analysis identified immune activation in Cluster 1, epithelial-mesenchymal transition (EMT) in Cluster 2, and cell cycle processes in Cluster 3. Notably, the impact of EMT activity on prognosis may vary across NB subtypes. A classification model using XGBoost accurately predicted subtypes in independent NB cohorts, with significant prognostic differences. GPR125, CDK4, and GREB1 emerged as potential therapeutic targets in Cluster 3. CD4K inhibitors showed subtype-specific responses, suggesting tailored treatment strategies. Single-cell analysis highlighted unfavorable clinical features in Cluster 3, including high-risk classification and reduced cytotoxicity. Suppressed interactions between monocytes, macrophages, and regulatory T cells were observed, affecting immune regulation and patient prognosis.ConclusionTo summarize, we have identified a new independent prognostic factor in NB that underscores the significant correlation between tumor phenotype and immune contexture. These findings deepen our understanding of NB subtypes and immune cell interactions, paving the way for more effective treatment approaches.

Project description:BackgroundBiomarkers based on immune context may guide prognosis prediction. T-cell inactivation, exclusion, or dysfunction could cause unfavorable tumor microenvironments, which affect immunotherapy and prognosis. However, none of the immuno-biomarkers reported to date can differentiate colorectal-cancer (CRC) patients. Thus, we aimed to classify CRC patients according to the levels of T-cell activation, exclusion, and dysfunction in the tumor microenvironment.MethodsRNAseq data of 618 CRC patients from The Cancer Genome Atlas and microarray data of 316 CRC patients from Gene Expression Omnibus were analysed using the Tumor Immune Dysfunction and Exclusion algorithm. Unsupervised clustering was used to classify patients.ResultsBased on the expression signatures of myeloid-derived suppressor cells, cancer-associated fibroblasts, M2-like tumor-associated macrophages, cytotoxic T-lymphocytes, and PD-L1, all patients were clustered into four subtypes: cluster 1 had a high level of immune dysfunction, cluster 2 had a low level of immune activation, cluster 3 had intense immune exclusion, and cluster 4 had a high level of immune activation and a moderate level of both dysfunction and exclusion signatures. Compared with cluster 1, the hazard ratios and 95% confidential intervals for overall survival were 0.63 (0.35-1.13) for cluster 2, 0.55 (0.29-1.03) for cluster 3, and 0.30 (0.14-0.64) for cluster 4 in multivariate Cox regression. Similar immune clustering and prognosis patterns were obtained upon validation in the GSE39582 cohort. In subgroup analysis, immune clustering was significantly associated with overall survival among stage I/II patients, microsatellite stable/instability-low patients, and patients not treated with adjuvant therapy.ConclusionsOur findings demonstrated that classifying CRC patients into different immune subtypes serves as a reliable prognosis predictor and may help to refine patient selection for personalized cancer immunotherapy.

Dataset Information

Unraveling tumour microenvironment heterogeneity in nasopharyngeal carcinoma identifies biologically distinct immune subtypes predicting prognosis and immunotherapy responses.

Publications

Unraveling tumour microenvironment heterogeneity in nasopharyngeal carcinoma identifies biologically distinct immune subtypes predicting prognosis and immunotherapy responses.

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