Dataset Information

Correlation Between Tumor-Associated Macrophage and Immune Checkpoint Molecule Expression and Its Prognostic Significance in Cutaneous Melanoma.

ABSTRACT: The association between tumor-associated macrophages (TAMs) and the expression of immune checkpoint molecules has not been well described in cutaneous melanoma. We evaluated the correlations between the expression of markers of TAMs, cluster of differentiation 163 (CD163), and immune checkpoint molecules, programmed cell death protein-1 (PD-1), and lymphocyte activating gene-3 (LAG-3). We also determined their relationships with the clinicopathological features and disease outcomes in melanoma. Diagnostic tissues collected from melanoma patients were evaluated using immunohistochemistry for CD163, PD-1, and LAG-3 expression. CD163 expression positively correlated with PD-1 and LAG-3 expression. High expression of both CD163 and PD-1 expressions was significantly associated with negative prognostic factors and worse prognosis than high expression of the single markers. High co-expression of CD163 and LAG-3 was associated with poor clinicopathological indexes of melanoma and worse survival compared to the high expression of the single markers. The expression of immune checkpoint molecules PD-1 and LAG-3 positively correlated with the M2-TAM density in melanoma tissue. Simultaneous high M2-TAM density and immune checkpoint molecules expression acted as independent poor prognostic factors in cutaneous melanoma.

SUBMITTER: Kim YJ

PROVIDER: S-EPMC7465191 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Correlation Between Tumor-Associated Macrophage and Immune Checkpoint Molecule Expression and Its Prognostic Significance in Cutaneous Melanoma.

Kim Young Jae YJ Won Chong Hyun CH Lee Mi Woo MW Choi Jee Ho JH Chang Sung Eun SE Lee Woo Jin WJ

Journal of clinical medicine 20200803 8

The association between tumor-associated macrophages (TAMs) and the expression of immune checkpoint molecules has not been well described in cutaneous melanoma. We evaluated the correlations between the expression of markers of TAMs, cluster of differentiation 163 (CD163), and immune checkpoint molecules, programmed cell death protein-1 (PD-1), and lymphocyte activating gene-3 (LAG-3). We also determined their relationships with the clinicopathological features and disease outcomes in melanoma. ...[more]

PMID: 32756500

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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: Little is known about the prognostic significance of somatically mutated genes in metastatic melanoma (MM). We have employed a combined clinical and bioinformatics approach on tumor samples from cutaneous melanoma (SKCM) as part of The Cancer Genome Atlas project (TCGA) to identify mutated genes with potential clinical relevance. Methods: After limiting our DNA sequencing analysis to MM samples (n = 356) and to the CANCER CENSUS gene list, we filtered out mutations with low functional significance (snpEFF). We performed Cox analysis on 53 genes that were mutated in ≥3% of samples, and had ≥50% difference in incidence of mutations in deceased subjects versus alive subjects. Results: Four genes were potentially prognostic [RAC1, FGFR1, CARD11, CIITA; false discovery rate (FDR) < 0.2]. We identified 18 additional genes (e.g., SPEN, PDGFRB, GNAS, MAP2K1, EGFR, TSC2) that were less likely to have prognostic value (FDR < 0.4). Most somatic mutations in these 22 genes were infrequent (< 10%), associated with high somatic mutation burden, and were evenly distributed across all exons, except for RAC1 and MAP2K1. Mutations in only 9 of these 22 genes were also identified by RNA sequencing in >75% of the samples that exhibited corresponding DNA mutations. The low frequency, UV signature type and RNA expression of the 22 genes in MM samples were confirmed in a separate multi-institution validation cohort (n = 413). An underpowered analysis within a subset of this validation cohort with available patient follow-up (n = 224) showed that somatic mutations in SPEN and RAC1 reached borderline prognostic significance [log-rank favorable (p = 0.09) and adverse (p = 0.07), respectively]. Somatic mutations in SPEN, and to a lesser extent RAC1, were not associated with definite gene copy number or RNA expression alterations. High (>2+) nuclear plus cytoplasmic expression intensity for SPEN was associated with longer melanoma-specific overall survival (OS) compared to lower (≤ 2+) nuclear intensity (p = 0.048). We conclude that expressed somatic mutations in infrequently mutated genes beyond the well-characterized ones (e.g., BRAF, RAS, CDKN2A, PTEN, TP53), such as RAC1 and SPEN, may have prognostic significance in MM.

Dataset Information

Correlation Between Tumor-Associated Macrophage and Immune Checkpoint Molecule Expression and Its Prognostic Significance in Cutaneous Melanoma.

Publications

Correlation Between Tumor-Associated Macrophage and Immune Checkpoint Molecule Expression and Its Prognostic Significance in Cutaneous Melanoma.

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