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Quantitative Analysis of Immune Infiltrates in Primary Melanoma.

ABSTRACT: Novel methods to analyze the tumor microenvironment (TME) are urgently needed to stratify melanoma patients for adjuvant immunotherapy. Tumor-infiltrating lymphocyte (TIL) analysis, by conventional pathologic methods, is predictive but is insufficiently precise for clinical application. Quantitative multiplex immunofluorescence (qmIF) allows for evaluation of the TME using multiparameter phenotyping, tissue segmentation, and quantitative spatial analysis (qSA). Given that CD3+CD8+ cytotoxic lymphocytes (CTLs) promote antitumor immunity, whereas CD68+ macrophages impair immunity, we hypothesized that quantification and spatial analysis of macrophages and CTLs would correlate with clinical outcome. We applied qmIF to 104 primary stage II to III melanoma tumors and found that CTLs were closer in proximity to activated (CD68+HLA-DR+) macrophages than nonactivated (CD68+HLA-DR-) macrophages (P < 0.0001). CTLs were further in proximity from proliferating SOX10+ melanoma cells than nonproliferating ones (P < 0.0001). In 64 patients with known cause of death, we found that high CTL and low macrophage density in the stroma (P = 0.0038 and P = 0.0006, respectively) correlated with disease-specific survival (DSS), but the correlation was less significant for CTL and macrophage density in the tumor (P = 0.0147 and P = 0.0426, respectively). DSS correlation was strongest for stromal HLA-DR+ CTLs (P = 0.0005). CTL distance to HLA-DR- macrophages associated with poor DSS (P = 0.0016), whereas distance to Ki67- tumor cells associated inversely with DSS (P = 0.0006). A low CTL/macrophage ratio in the stroma conferred a hazard ratio (HR) of 3.719 for death from melanoma and correlated with shortened overall survival (OS) in the complete 104 patient cohort by Cox analysis (P = 0.009) and merits further development as a biomarker for clinical application. Cancer Immunol Res; 6(4); 481-93. ©2018 AACR.

SUBMITTER: Gartrell RD

PROVIDER: S-EPMC5882545 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Quantitative Analysis of Immune Infiltrates in Primary Melanoma.

Gartrell Robyn D RD Marks Douglas K DK Hart Thomas D TD Li Gen G Davari Danielle R DR Wu Alan A Blake Zoë Z Lu Yan Y Askin Kayleigh N KN Monod Anthea A Esancy Camden L CL Stack Edward C EC Jia Dan Tong DT Armenta Paul M PM Fu Yichun Y Izaki Daisuke D Taback Bret B Rabadan Raul R Kaufman Howard L HL Drake Charles G CG Horst Basil A BA Saenger Yvonne M YM

Cancer immunology research 20180221 4

Novel methods to analyze the tumor microenvironment (TME) are urgently needed to stratify melanoma patients for adjuvant immunotherapy. Tumor-infiltrating lymphocyte (TIL) analysis, by conventional pathologic methods, is predictive but is insufficiently precise for clinical application. Quantitative multiplex immunofluorescence (qmIF) allows for evaluation of the TME using multiparameter phenotyping, tissue segmentation, and quantitative spatial analysis (qSA). Given that CD3<sup>+</sup>CD8<sup> ...[more]

PMID: 29467127

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Project description:BackgroundSkin cutaneous melanoma (SKCM) is a highly malignant skin tumor. DIRAS2 is considered to be a tumor suppressor gene; however, its function in SKCM has not been explored.MethodsThe Gene Expression Profiling Interactive Analysis (GEPIA) was implemented to investigate the expression of DIRAS2 in SKCM, and plot the survival curve to determine the effect of DIRAS2 on the survival rates of SKCM patients. Then, the correlation between DIRAS2 and tumor immune infiltration was also discussed, and the expression of DIRAS2 and immune infiltration level in SKCM immune cells was determined using TIMER. The top 100 genes most associated with DIRAS2 expression were used for functional enrichment analysis. In order to confirm the anti-cancer effects of DIRAS2 in SKCM in the data analysis, in vitro assays as well as in vivo studies of DIRAS2 on SKCM tumor cell proliferation, migration, invasion, and metastasis were conducted. Western blot and immunofluorescence assay were employed to study the relationship between DIRAS2 and Wnt/β-catenin signaling pathway in SKCM.ResultsDIRAS2 expression was shown to be significantly correlated with tumor grade using univariate logistic regression analysis. DIRAS2 was found to be an independent prognostic factor for SKCM in multivariate analysis. Of note, DIRAS2 expression levels were positively correlated with the infiltration levels of B cells, CD4+ T cells, and CD8+ T cells in SKCM. The infiltration of B cells, CD4+ T cells, and CD8+ T cells was positively correlated with the cumulative survival rate of SKCM patients. In vitro experiments suggested that proliferation, migration, invasion, and metastasis of SKCM tumor cells were distinctly enhanced after DIRAS2 knockdown. Furthermore, DIRAS2 depletion promoted melanoma growth and metastasis in vivo. As for the mechanism, silencing DIRAS2 can activate the signal transduction of the Wnt/β-catenin signaling pathway.ConclusionDIRAS2 functions as a tumor suppressor gene in cases of SKCM by inhibiting the Wnt/β-catenin signaling. It is also associated with immune infiltration in SKCM.

Project description:BackgroundAs a member of tumor, Skin cutaneous melanoma (SKCM) poses a serious threat to people's health because of its strong malignancy. Unfortunately, effective treatment methods for SKCM remain lacking. FANCI plays a vital role in the occurrence and metastasis of various tumor types. However, its regulatory role in SKCM is unclear. The purpose of this study was to explore the association of FANCI with SKCM.MethodsThis study investigated the expression of FANCI in GSE46517, GSE15605, and GSE114445 from the Gene Expression Omnibus database and The Cancer Genome Atlas (TCGA)-SKCM datasets using the package "limma" or "DESeq2" in R environment and also investigated the prognostic significance of FANCI by utilizing the GEPIA database. Additionally, our research made use of real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical (IHC) staining to verify FANCI expression between SKCM and normal tissues and developed the knockdown of FANCI in A375 and A875 cells to further analyze the function of FANCI. Finally, this study analyzed the correlation of FANCI and tumor-infiltrating immune cells by CIBERSORT, ESTIMATE, and ssGSEA algorithms.ResultsThe FANCI level was increasing in SKCM tissues from GSE46517, GSE15605, GSE114445, and TCGA-SKCM. However, high FANCI expression correlated with poor overall survival. The RT-qPCR and IHC confirmed the accuracy of bioinformatics. Knocking down FANCI suppresses A375 and A875 cell proliferation, migration, and invasion. FANCI could be involved in the immunological milieu of SKCM by regulating immune responses and infiltrating numerous immune cells, particularly neutrophils, CD8+ T cells, and B cells. Furthermore, patients with SKCM who have a high FANCI expression level are reported to exhibit immunosuppression, whereas those with a low FANCI expression level are more likely to experience positive outcomes from immunotherapy.ConclusionsThe increased FANCI expression in SKCM can be a prognostic biomarker. Knockdown FANCI can reduce the occurrence and progression of SKCM. The FANCI expression provides a foundation for predicting the immune status and treatment of SKCM.

Dataset Information

Quantitative Analysis of Immune Infiltrates in Primary Melanoma.

Publications

Quantitative Analysis of Immune Infiltrates in Primary Melanoma.

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