Analysis of the immune landscape in virus-induced cancers using a novel integrative mechanism discovery approach

Wong, Lauren; Li, Wei Tse; Shende, Neil; Tsai, Joseph C.; Ma, Jiayan; Chakladar, Jaideep; Gnanasekar, Aditi; Qu, Yuanhao; Dereschuk, Kypros; Wang‐Rodriguez, Jessica; Ongkeko, Weg M.

doi:10.1016/j.csbj.2021.11.013

Cited by 3 publications

(3 citation statements)

References 24 publications

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“…Despite the well understood differences in the pathological [ 41 , 42 ] and clinical outcomes [ 43 , 44 , 45 ] between EBVaGCs and EBVnGCs, comparisons of their respective tumor immune microenvironments are generally restricted to a subset of markers in a subset of subtypes [ 46 , 47 , 48 , 49 , 50 ]. There is ever increasing evidence that patient outcomes are greatly impacted by the interactions of tumors with their local immune microenvironments [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Tumor-Infiltrating T Cells in EBV-Associated Gastric Carcinomas Exhibit High Levels of Multiple Markers of Activation, Effector Gene Expression, and Exhaustion

Salnikov

Prusinkiewicz

Lin

et al. 2023

Viruses

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Epstein–Barr virus (EBV) is a gamma-herpesvirus associated with 10% of all gastric cancers (GCs) and 1.5% of all human cancers. EBV-associated GCs (EBVaGCs) are pathologically and clinically distinct entities from EBV-negative GCs (EBVnGCs), with EBVaGCs exhibiting differential molecular pathology, treatment response, and patient prognosis. However, the tumor immune landscape of EBVaGC has not been well explored. In this study, a systemic and comprehensive analysis of gene expression and immune landscape features was performed for both EBVaGC and EBVnGC. EBVaGCs exhibited many aspects of a T cell-inflamed phenotype, with greater T and NK cell infiltration, increased expression of immune checkpoint markers (BTLA, CD96, CTLA4, LAG3, PD1, TIGIT, and TIM3), and multiple T cell effector molecules in comparison with EBVnGCs. EBVaGCs also displayed a higher expression of anti-tumor immunity factors (PDL1, CD155, CEACAM1, galectin-9, and IDO1). Six EBV-encoded miRNAs (miR-BARTs 8-3p, 9-5p, 10-3p, 22, 5-5p, and 14-3p) were strongly negatively correlated with the expression of immune checkpoint receptors and multiple markers of anti-tumor immunity. These profound differences in the tumor immune landscape between EBVaGCs and EBVnGCs may help explain some of the observed differences in pathological and clinical outcomes, with an EBV-positive status possibly being a potential biomarker for the application of immunotherapy in GC.

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Section: Discussionmentioning

confidence: 99%

Tumor-Infiltrating T Cells in EBV-Associated Gastric Carcinomas Exhibit High Levels of Multiple Markers of Activation, Effector Gene Expression, and Exhaustion

Salnikov

Prusinkiewicz

Lin

et al. 2023

Viruses

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“…From pathway enrichment analysis, we found that early stages of invasive CeCa differed from their non-invasive precursor lesions in marked up-regulation of innate immunity pathways, particularly antiviral mechanisms mediated by DNA-sensors, and involvement of IFN-stimulated, pro-inflammatory, as well as DDR-related genes. This probably implies that overstimulation of protective mechanisms in early periods may be one of the triggers and contributors of invasion; at subsequent stages this could become manifest in the form of an immune-active but chronically inflamed and exhausted molecular subtype (43)(44)(45). Relatedness of the DDR-associated processes and "heating-up" the immune TME has also been underscored by some researchers (42,(46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

Sequencing-based transcriptome analysis reveals diversification of immune response- and angiogenesis-related expression patterns of early-stage cervical carcinoma as compared with high-grade CIN

Kurmyshkina,

Dobrynin,

Kovchur

et al. 2023

Front. Immunol.

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BackgroundMolecular diversity of virus-associated cervical cancer remains a relatively underexplored issue, and interrelations of immunologic and angiogenic features during the establishment of a particular landscape of the cervical cancer microenvironment are not well-characterized, especially for its earliest clinical stages, although this may provide insight into the mechanisms behind the differences in tumor aggressiveness, treatment responsiveness and prognosis. In this research, we were aimed at identifying transcriptomic landscapes of early-stage cervical carcinoma that differ substantially in their immune-related characteristics, patterns of signaling pathways and composition of the microenvironment in comparison with immediate precursor (intraepithelial) lesions.MethodsWe performed the Illumina platform-based RNA sequencing using a panel of fresh tissue samples that included human papillomavirus-positive cervical intraepithelial neoplastic lesions (CIN), invasive squamous carcinoma of the cervix of FIGO IA1-IIB stages, and morphologically normal epithelium. The derived transcriptomic profiles were bioinformatically analyzed and compared by patterns of signaling pathway activation, distribution of tumor-infiltrating cell populations, and genomic regions involved.ResultAccording to hierarchical cluster analysis of the whole-transcriptome profiles, tissue samples were distributed between three groups, or gene expression patterns (the one comprising most pre-cancer cases and the other two encompassing mostly early-stage invasive cancer cases). Differentially expressed genes were retrieved in each intergroup pairwise comparison followed by Gene Ontology analysis. Gene set enrichment analysis of the two groups of tumor samples in comparison with the CIN group identified substantial differences in immunological and angiogenic properties between tumorous groups suggesting the development of different molecular phenotypes. Cell composition analysis confirmed the diverse changes in the abundancies of immune and non-immune populations and, accordingly, different impacts of the immune and stromal compartments on the tumor microenvironment in these two groups of tumors compared to CIN. Positional gene expression analysis demonstrated that the identified transcriptomic differences were linked to different chromosomal regions and co-localized with particular gene families implicated in immune regulation, inflammation, cell differentiation, and tumor invasion.ConclusionsOverall, detection of different transcriptomic patterns of invasive cervical carcinoma at its earliest stages supports the diverse impacts of immune response- and angiogenesis-related mechanisms on the onset of tumor invasion and progression. This may provide new options for broadening the applicability and increasing the efficiency of target anti-angiogenic and immune-based therapy of virus-associated cervical carcinoma.

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“…CC ranks in the top ten female cancers in incidence and mortality in California and Texas [ 1 ]. Various studies have shown that the alteration in gene expression is an important event in CC [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of Mir-182-3p/FLI-1 Axis as a Key Signaling in Immune Response in Cervical Cancer: A Comprehensive Bioinformatic Analysis

Salmerón-Bárcenas

Mendoza-Catalán

Ramírez-Bautista

et al. 2023

IJMS

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miRNAs modulate gene expression and play critical functions as oncomiRs or tumor suppressors. The miR-182-3p is important in chemoresistance and cancer progression in breast, lung, osteosarcoma, and ovarian cancer. However, the role of miR-182-3p in cervical cancer (CC) has not been elucidated. Aim: To analyze the role of miR-182-3p in CC through a comprehensive bioinformatic analysis. Methods: Gene Expression Omnibus (GEO) databases were used for the expression analysis. The mRNA targets of miR-182-3p were identified using miRDB, TargetScanHuman, and miRPathDB. The prediction of island CpG was performed using the MethPrimer program. The transcription factor binding sites in the FLI-1 promoter were identified using ConSite+, Alibaba2, and ALGGEN-PROMO. The protein–protein interaction (PPI) analysis was performed in STRING 11.5. Results: miR-182-3p was significantly overexpressed in CC patients and has potential as a diagnostic. We identified 330 targets of miR-182-3p including FLI-1, which downregulates its expression in CC. Additionally, the aberrant methylation of the FLI-1 promoter and Ap2a transcription factor could be involved in downregulating FLI1 expression. Finally, we found that FLI-1 is a possible key gene in the immune response in CC. Conclusions: The miR-182-3p/FLI-1 axis plays a critical role in immune response in CC.

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Analysis of the immune landscape in virus-induced cancers using a novel integrative mechanism discovery approach

Abstract: Graphical abstract

Cited by 3 publications

References 24 publications

Tumor-Infiltrating T Cells in EBV-Associated Gastric Carcinomas Exhibit High Levels of Multiple Markers of Activation, Effector Gene Expression, and Exhaustion

Tumor-Infiltrating T Cells in EBV-Associated Gastric Carcinomas Exhibit High Levels of Multiple Markers of Activation, Effector Gene Expression, and Exhaustion

Sequencing-based transcriptome analysis reveals diversification of immune response- and angiogenesis-related expression patterns of early-stage cervical carcinoma as compared with high-grade CIN

Identification of Mir-182-3p/FLI-1 Axis as a Key Signaling in Immune Response in Cervical Cancer: A Comprehensive Bioinformatic Analysis

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