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Inflammation and lymphocyte infiltration are associated with shorter survival in patients with high-grade glioma.

ABSTRACT: Glioma represents a serious health burden in terms of morbidity and mortality. The prognostic significance of the lymphoid and myeloid infiltrates in glioma is not clearly determined. Moreover, the characterization of different leukocyte subsets in the tumor microenvironment relies mainly on immunohistochemistry observations, and data about their association with prognosis are contradictory. Here, we performed acomprehensive study of both the tumor-infiltrating and circulating immune compartments of patients with high-grade glioma. Nineteen tumor biopsies and 30 PBMC samples were analyzed by RNA sequencing. Validation was performed on The Cancer Genome Atlas (TCGA) RNA sequencing data from glioma and on additional 39 tumor biopsies analyzed by flow cytometry. We identified prognostic tumor and peripheral immune signatures, which associate increased inflammation, immune infiltration and activation with shorter overall survival in high-grade glioma patients. Importantly, we confirmed our observations by flow cytometry analysis and validated the tumor-signature using the TCGA dataset. In addition, both tumor genotype and grade associated with the degree of glioma immune infiltration. Unlike in the majority of cancers, lymphocyte infiltration at the tumor site is anegative prognostic factor in glioma, suggesting the ambivalent pro-tumorigenic role of immune responses in glioma.

SUBMITTER: Marinari E

PROVIDER: S-EPMC7458651 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Inflammation and lymphocyte infiltration are associated with shorter survival in patients with high-grade glioma.

Marinari Eliana E Allard Mathilde M Gustave Robin R Widmer Valérie V Philippin Géraldine G Merkler Doron D Tsantoulis Petros P Dutoit Valérie V Dietrich Pierre-Yves PY

Oncoimmunology 20200621 1

Glioma represents a serious health burden in terms of morbidity and mortality. The prognostic significance of the lymphoid and myeloid infiltrates in glioma is not clearly determined. Moreover, the characterization of different leukocyte subsets in the tumor microenvironment relies mainly on immunohistochemistry observations, and data about their association with prognosis are contradictory. Here, we performed acomprehensive study of both the tumor-infiltrating and circulating immune compartment ...[more]

PMID: 32923142

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Project description:BackgroundDiffuse gliomas (WHO grade II-IV) are progressive primary brain tumors with great variability in prognosis. Cognitive deficits are of important prognostic value for survival in diffuse gliomas. Until now, few studies focused on domain-specific neuropsychological assessment and rather used MMSE as a measure for cognitive functioning. Additionally, these studies did not take WHO 2016 diagnosis into account. We performed a retrospective cohort study with the aim to investigate the independent relationship between cognitive functioning and survival in treatment-naive patients undergoing awake surgery for a diffuse glioma.MethodsIn patients undergoing awake craniotomy between 2010 and 2017, we performed pre-operative neuropsychological assessments in five cognitive domains, with special attention for the domains executive functioning and memory. We evaluated the independent relation between these domains and survival, in a Cox proportional hazards model that included state-of-the-art integrated histomolecular ('layered' or WHO-2016) classification of the gliomas and other known prognostic factors.ResultsWe included 197 patients. Cognitive impairments (Z-values ≦ - 2.0) were most frequent in the domains memory (18.3%) and executive functioning (25.9%). Impairments in executive functioning and memory were significantly correlated with survival, even after correcting for the possible confounders. Analyses with the domains language, psychomotor speed, and visuospatial functioning yielded no significant results. Extensive domain-specific neuropsychological assessment was more strongly correlated to survival than MMSE.ConclusionCognitive functioning is independently related to survival in diffuse glioma patients. Possible mechanisms underlying this relationship include the notion of cognitive functioning as a marker for diffuse infiltration of the tumor and the option that cognitive functioning and survival are determined by overlapping genetic pathways and biomarkers.

Project description:Background/Objectives: High-grade gliomas are the most common primary malignant brain tumors in adults. These neoplasms remain predominantly incurable due to the genetic diversity within each tumor, leading to varied responses to specific drug therapies. With the advent of new targeted and immune therapies, which have demonstrated promising outcomes in clinical trials, there is a growing need for image-based techniques to enable early prediction of treatment response. This study aimed to evaluate the potential of radiomics and artificial intelligence implementation in predicting progression-free survival (PFS) in patients with highest-grade glioma (CNS WHO 4) undergoing a standard treatment plan. Methods: In this retrospective study, prediction models were developed in a cohort of 51 patients with pathologically confirmed highest-grade glioma (CNS WHO 4) from the authors' institution and the repository of the Cancer Imaging Archive (TCIA). Only patients with confirmed recurrence after complete tumor resection with adjuvant radiotherapy and chemotherapy with temozolomide were included. For each patient, 109 radiomic features of the tumor were obtained from a preoperative magnetic resonance imaging (MRI) examination. Four clinical features were added manually-sex, weight, age at the time of diagnosis, and the lobe of the brain where the tumor was located. The data label was the time to recurrence, which was determined based on follow-up MRI scans. Artificial intelligence algorithms were built to predict PFS in the training set (n = 75%) and then validate it in the test set (n = 25%). The performance of each model in both the training and test datasets was assessed using mean absolute percentage error (MAPE). Results: In the test set, the random forest model showed the highest predictive performance with 1-MAPE = 92.27% and a C-index of 0.9544. The decision tree, gradient booster, and artificial neural network models showed slightly lower effectiveness with 1-MAPE of 88.31%, 80.21%, and 91.29%, respectively. Conclusions: Four of the six models built gave satisfactory results. These results show that artificial intelligence models combined with radiomic features could be useful for predicting the progression-free survival of high-grade glioma patients. This could be beneficial for risk stratification of patients, enhancing the potential for personalized treatment plans and improving overall survival. Further investigation is necessary with an expanded sample size and external multicenter validation.

Project description:BackgroundTyrosine protein tyrosine kinase binding protein (TYROBP) binds non-covalently to activated receptors on the surface of various immune cells, and mediates signal transduction and cellular activation. It is dysregulated in various malignancies, although little is known regarding its role in low-grade glioma. The aim of this study is to explore the clinicopathological significance, prognostic value and immune signature of TYROBP expression in low-grade glioma (LGG).MethodsThe differentially expressed genes (DEGs) between glioma samples and normal tissues were identified from two GEO microarray datasets using the limma package. The DEGs overlapping across both datasets were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. STRING database was used to establish the protein-protein interaction (PPI) of the DEGs. The PPI network was visualized by Cytoscape and cytoHubba, and the core module and hub genes were identified. The expression profile of TYROBP and patient survival were validated in the Oncomine, GEPIA2 and CGGA databases. The correlation between TYROBP expression and the clinicopathologic characteristics were evaluated. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were performed by R based on the LGG data from TCGA. The TIMER2.0 database was used to determine the correlation between TYROBP expression and tumor immune infiltrating cells in the LGG patients. Univariate and multivariate Cox regression analyses were performed to determine the prognostic impact of clinicopathological factors via TCGA database.ResultsSixty-two overlapping DEGs were identified in the 2 datasets, and were mainly enriched in the response to wounding, focal adhesion, GTPase activity and Parkinson disease pathways. TYROBP was identified through the PPI network and cytoHubba. TYROBP expression levels were significantly higher in the LGG tissues compared to the normal tissues, and was associated with worse prognosis and poor clinicopathological parameters. In addition, GSEA showed that TYROBP was positively correlated to neutrophil chemotaxis, macrophage activation, chemokine signaling pathway, JAK-STAT signaling pathway, and negatively associated with gamma aminobutyric acid signaling pathway, neurotransmitter transport, neuroactive ligand receptor intersection etc. TIMER2.0 and ssGSEA showed that TYROBP expression was significantly associated with the infiltration of neutrophils, macrophages, myeloid dendritic cells and monocytes. The infiltration of the M2 phenotype macrophages, cancer-associated fibroblasts and myeloid dendritic cells correlated to worse prognosis in LGG patients. Finally, multivariate analysis showed that elevated TYROBP expression is an independent risk factor for LGG.ConclusionTYROBP is dysregulated in LGG and correlates with immune infiltration. It is a potential therapeutic target and prognostic marker for LGG.

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Inflammation and lymphocyte infiltration are associated with shorter survival in patients with high-grade glioma.

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Inflammation and lymphocyte infiltration are associated with shorter survival in patients with high-grade glioma.

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