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Comprehensive Analysis of the Tumor Microenvironment in Cutaneous Melanoma associated with Immune Infiltration.

ABSTRACT: Accumulating evidence suggests that the malignant phenotypes of cancers are determined not only by the intrinsic properties of cancer cells but also by components in the tumor microenvironment (TME). In this study, we comprehensively characterized the TME of cutaneous melanoma (CM). As a result, tumor stage, tissue site, ulceration, thickness as well as patient age, sex were associated with immune infiltration. Patients of higher immune infiltration exhibited better survival outcomes, and antitumor effector cells, such as CD8 T cells and M1 macrophages, were found in significantly higher numbers in those tissues. Differential expression of mRNAs and long non-coding RNAs (lncRNAs) was analyzed and utilized to construct an immune-related competing endogenous RNA network, in which a lncRNA-associated subnetwork that could positively regulate the expression of IFN-? was highlighted. Functional analysis confirmed that this network was remarkably enriched in functional terms related to both immune response and tumor-intrinsic pathways. Finally, a total of 109 high-confidence prognostic genes were identified, and a gene module that contained several key immune checkpoint molecules or modulators (PD-1, PD-L1, PD-L2, and LCK) was screened, which confers survival benefit for CM patients as supported by both overall and relapse-free survival rates from different datasets.

SUBMITTER: Wang P

PROVIDER: S-EPMC7171484 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Comprehensive Analysis of the Tumor Microenvironment in Cutaneous Melanoma associated with Immune Infiltration.

Wang Pan P Zhang Xinyu X Sun Nan N Zhao Zhihong Z He Jie J

Journal of Cancer 20200406 13

Accumulating evidence suggests that the malignant phenotypes of cancers are determined not only by the intrinsic properties of cancer cells but also by components in the tumor microenvironment (TME). In this study, we comprehensively characterized the TME of cutaneous melanoma (CM). As a result, tumor stage, tissue site, ulceration, thickness as well as patient age, sex were associated with immune infiltration. Patients of higher immune infiltration exhibited better survival outcomes, and antitu ...[more]

PMID: 32328190

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Project description:BackgroundEven though immunotherapy has been an effective treatment for solid tumors, its efficacy in osteosarcoma remains sub-optimal. It is therefore imperative to understand the complex tumor microenvironment (TME) of osteosarcoma to facilitate the development of immunotherapies against this cancer.MethodsThe mRNA expression profiles of osteosarcoma tissues were downloaded from The Cancer Genome Atlas (TCGA) database. Next, the ssGSEA, MCP-counter, CIBERSORT, and Xcell algorithm analyses were performed to characterize the tumor microenvironment of osteosarcoma tissues. The tumor tissues were divided into inflammatory and non-inflammatory. A comprehensive assessment of immune cell infiltration in osteosarcoma tissues was then performed. Sub-group analysis of immune cell infiltration between men and women patients with osteosarcoma was also carried out.ResultsThe results revealed that the infiltration of immune cells including activated B cell, activated CD8 T cell, CD56dim natural killer cell, and cytotoxic lymphocytes cells, in osteosarcoma tissues was higher in male than in female patients. Based on the infiltration profile of different immune cells, the osteosarcoma tissues were grouped into four clusters. The four clusters were further divided into hot and cold tumors. The differently expressed genes (DEGs) between cold and hot tumors were mainly associated with the activation and regulation of immune response. Additionally, a neuronal pentraxin (NPTX2) expression which was upregulated in cold tumors was found to be negatively correlated with the expression of CD8a Molecule (CD8A), Granzyme B (GZMB), and Interferon Gamma (IFNG). NPTX2 decreased CCL4 secretion. Knockdown of NPTX2 in osteosarcoma cells inhibited tumor growth and increased tumor cell apoptosis. Moreover, a prognosis prediction model of osteosarcoma was constructed and validated in patients receiving immunotherapy using external data.ConclusionsTo the best of our knowledge, this is the first study to characterize the infiltration of immune cells in osteosarcoma tissues from patients receiving immune infiltration therapy.

Project description:Background: Melanoma is highly immunogenic and therefore suitable for immunotherapy, but the efficacy is limited by response rate. In several types of tumor, tumor mutation burden (TMB) and immune infiltration have been reported to predict the response to immunotherapy, although each has its limitations. In the current study, we aimed to explore the association of TMB with immune infiltration and prognosis in cutaneous melanoma. Methods: The data of cutaneous melanoma used for analyses was downloaded from The Cancer Genome Atlas (TCGA) database. The mutation data was sorted using "maftools" R package. TMB was estimated and then patients were divided into two groups based on TMB. The association of TMB with prognosis and clinical characteristics was explored. Differential analysis between two TMB groups was performed using "DESeq2" R package to identify differentially expressed genes (DEGs). The function enrichment analyses of DEGs were conducted to screen critical pathways. Besides, DEGs were further filtered to identify two hub genes, based on which a risk score model and nomogram for predicting prognosis were conducted, and the validation was performed using three datasets from Gene Expression Omnibus (GEO) database. Finally, CIBERSORT algorithm and TIMER database were used to assess the effect of TMB and hub genes on immune infiltration. Results: The most common mutation was C > T, and the top three frequently mutated genes were TTN, MUC16, and BRAF. Higher TMB indicated better survival outcomes and lower pathological stages. 735 DEGs were identified and mainly involved in immune-related and adhesion-related pathways. The risk score model and nomogram were validated using receiver operating characteristic (ROC) curves and calibration curves, and exhibited relatively high predictive capability. Decision curve analysis (DCA) was used to assess clinical benefit. As for immune infiltration, the proportion was higher for macrophages M1 and M2 in the high-TMB group, while lower for memory B cells and regulatory T cells. Conclusions: In cutaneous melanoma, TMB was positively correlated with prognosis. The risk score model and nomogram can be conveniently used to predict prognosis. The association of TMB with immune infiltration can help improve the predicting methods for the response to immunotherapy.

Project description:Background: Immunotherapy elicits durable responses in many tumors. Nevertheless, the positive response to immunotherapy always depends on the dynamic interactions between the tumor cells and infiltrating lymphocytes in the tumor microenvironment (TME). Currently, the application of immunotherapy in hepatocellular carcinoma (HCC) has achieved limited success. The ectopic modification of N6-methyladenosine (m6A) is a common feature in multiple tumors. However, the relationship between m6A modification with HCC clinical features, prognosis, immune cell infiltration, and immunotherapy efficacy remains unclear. Materials and Methods: Here, we comprehensively evaluated m6A modification clusters based on 22 m6A regulators and systematically explored the relationship between m6A modification with tumor progression, prognosis, and immune cell infiltration characteristics. The m6Ascore was calculated by principal component analysis to quantify the m6A modifications of individual patients. Key regulators involved in immunoregulation in HCC were identified using immunohistochemistry and immunofluorescence. Results: Three distinct m6A modification clusters were identified. The m6A clusters were significantly associated with clinical features, prognosis, and immune cell infiltration. The three clusters were highly consistent with the three tumor immune phenotypes, i.e., immune-excluded, immune-inflamed, and immune-desert. Comprehensive bioinformatics analysis revealed that high m6Ascore was closely associated with tumor progression, poor prognosis, and immunotherapy non-response. m6A regulators were dysregulated in HCC tissues. Hence, they play a role as predictors of poor prognosis. Tissue microarray demonstrated that overexpressed YTHDF1 was associated with low CD3+ and CD8+ T cell infiltration in HCC. Conclusion: Our findings demonstrate that m6A modification patterns play a crucial role in the tumor immune microenvironment and the prognosis of HCC. High YTHDF1 expression is closely associated with low CD3+ and CD8+ T cell infiltration in HCC.

Project description:The neutrophils exhibit both anti-tumor and pro-tumor effects in cancers. The correlation between neutrophils and tumor development in lung adenocarcinoma (LUAD) is still uncertain, possibly due to a lack of specific neutrophil infiltration evaluation methods. In this study, we identified 30 hub genes that were significantly associated with neutrophil infiltration in LUAD through data mining, survival analysis, and multiple tumor-infiltrating immune cells (TICs) analysis, including TIMER, CIBERSORT, QUANTISEQ, XCELL, and MCPCOUNTER. Consensus clustering analysis showed that these 30 hub genes were correlated with clinical features in LUAD. We further developed a neutrophil scoring system based on these hub genes. The neutrophil score was significantly correlated with prognosis and tumor immune microenvironment (TIME) in LUAD. It was also positively associated with PD-L1 expression and negatively associated with tumor mutational burden (TMB). When combined with the neutrophil score, the predictive capacity of PD-L1 and TMB for prognosis was significantly improved. Thus, the 30 hub genes might play an essential role in the interaction of neutrophils and LUAD, and the neutrophil scoring system might effectually assess the infiltration of neutrophils. Furthermore, we verified the expression of these 30 genes in the LUAD tumor tissues collected from our department. We further found that overexpressed TNFAIP6 and TLR6 and downregulated P2RY13, SCARF1, DPEP2, PRAM1, CYP27A1, CFP, GPX3, and NCF1 in LUAD tissue might be potentially associated with neutrophils pro-tumor effects. The following in vitro experiments demonstrated that TNFAIP6 and TLR6 were significantly overexpressed, and P2RY13 and CYP27A1 were significantly downregulated in LUAD cell lines, compared to BEAS-2B cells. Knocking down TNFAIP6 in A549 and PC9 resulted in the upregulation of FAS, CCL3, and ICAM-1, and the downregulation of CCL2, CXCR4, and VEGF-A in neutrophils when co-culturing with the conditioned medium (CM) from LUAD cells. Knocking down TNFAIP6 in LUAD also led to an elevated early apoptosis rate of neutrophils. Therefore, overexpressed TNFAIP6 in LUAD cancer cells might lead to neutrophils "N2" polarization, which exhibited pro-tumor effects. Further research based on the genes identified in this pilot study might shed light on neutrophils' effects on LUAD in the future.

Dataset Information

Comprehensive Analysis of the Tumor Microenvironment in Cutaneous Melanoma associated with Immune Infiltration.

Publications

Comprehensive Analysis of the Tumor Microenvironment in Cutaneous Melanoma associated with Immune Infiltration.

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