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Immune Cytolytic Activity for Comprehensive Understanding of Immune Landscape in Hepatocellular Carcinoma.

ABSTRACT: Cytolytic activity score (CYT), defined by granzyme A and perforin expression, is a useful marker for underlying immunity. We hypothesized that CYT-high hepatocellular carcinomas (HCCs) have stronger immunogenicity and favorable tumor microenvironments, which would result in better clinical outcomes, using the cancer genome atlas (TCGA) cohort with 371 patients with HCC. We found CYT-high HCCs were associated with higher expressions of the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3), well-known mutagenic enzymes. Further, higher numbers of anti-cancer immune cells, such as CD8+ T cells and M1 macrophages, were infiltrated in CYT-high HCCs. Major T cell exhaustion markers were expressed significantly higher in CYT-high HCCs, likely as a negative feedback loop. Additionally, CYT-high HCCs strongly enriched gene sets related with enhanced immune activity. With strong immunity, patients with CYT-high HCCs had significantly longer disease-specific survival (DSS) and overall survival (OS) (p = 0.03?and <0.01). Furthermore, when the OS is stratified by exhaustion marker expressions, the CYT-high/exhaustion-low group had the best and CYT-low/exhaustion-high groups had the worst OS. Lastly, high CYT was an independent protective factor for prognosis. In conclusion, CYT-high HCCs were associated with enhanced immunity and better survival. Our findings suggest that proper identification of tumor-immune microenvironments could stratify the patients for appropriate treatments.

SUBMITTER: Takahashi H

PROVIDER: S-EPMC7281225 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Immune Cytolytic Activity for Comprehensive Understanding of Immune Landscape in Hepatocellular Carcinoma.

Takahashi Hideo H Kawaguchi Tsutomu T Yan Li L Peng Xuan X Qi Qianya Q Morris Luc G T LGT Chan Timothy A TA Tsung Allan A Otsuji Eigo E Takabe Kazuaki K

Cancers 20200513 5

Cytolytic activity score (CYT), defined by granzyme A and perforin expression, is a useful marker for underlying immunity. We hypothesized that CYT-high hepatocellular carcinomas (HCCs) have stronger immunogenicity and favorable tumor microenvironments, which would result in better clinical outcomes, using the cancer genome atlas (TCGA) cohort with 371 patients with HCC. We found CYT-high HCCs were associated with higher expressions of the apolipoprotein B mRNA editing enzyme catalytic polypepti ...[more]

PMID: 32414098

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Project description:Hepatocellular carcinoma (HCC) is one of the most common types of cancer diagnosed worldwide. After a decade of stagnation, several novel compounds have recently been shown to be effective in the treatment of HCC. Since immunotherapy is associated with important clinical benefits in some, but not all patients, it is essential to identify reliable predictive biomarkers. As the complex interplay between hepatocytes and immune cells is highly dependent on the tumor microenvironment, the tumor microenviroment has been suggested to be an important factor associated with the response to therapy and is currently being extensively investigated. Within this network, several important factors should be highlighted. Most of the cells are hepatocytes, but fibroblasts, endothelial cells, and immune cells are also present. Tumor-infiltrating leukocytes include several populations of cells and each of them plays a role in forming the tumor environment. Some of these cells may have antitumor effects, whereas others may be associated with the progression of the disease. The most important subsets include tumor-associated macrophages, tumor-associated neutrophils, and lymphocytes. These groups are described in the present review. The immune response is controlled by immune checkpoint molecules. One of the most important molecules involved in this checkpoint process seems to be the programmed death-1 (PD-1) receptor, which typically is induced on activated T cells, natural killer (NK) cells, B cells, and antigen-presenting cells. On the other hand, programmed death ligand 1 (PD-L1) is expressed by tumor cells, hepatocytes and hepatic stellate cells, and Kupffer cells or liver sinusoidal cells. Complex interactions between ligands and receptors are dependent on the signals from the microenvironment leading to either cancer development or apoptosis. Evidence from several studies indicates that patients with higher expression levels of PD-L1 on tumor cells or immune cells are more likely to achieve beneficial results from treatment with checkpoint blockers. This review focuses on the basic information regarding the microenvironment and its components, particularly on immune system involvement.

Project description:BackgroundHepatocellular carcinoma (HCC) is a complex disease with a poor outlook for patients in advanced stages. Immune cells play an important role in the progression of HCC. The metabolism of sphingolipids functions in both tumor growth and immune infiltration. However, little research has focused on using sphingolipid factors to predict HCC prognosis. This study aimed to identify the key sphingolipids genes (SPGs) in HCC and develop a reliable prognostic model based on these genes.MethodsThe TCGA, GEO, and ICGC datasets were grouped using SPGs obtained from the InnateDB portal. A prognostic gene signature was created by applying LASSO-Cox analysis and evaluating it with Cox regression. The validity of the signature was verified using ICGC and GEO datasets. The tumor microenvironment (TME) was examined using ESTIMATE and CIBERSORT, and potential therapeutic targets were identified through machine learning. Single-cell sequencing was used to examine the distribution of signature genes in cells within the TME. Cell viability and migration were tested to confirm the role of the key SPGs.ResultsWe identified 28 SPGs that have an impact on survival. Using clinicopathological features and 6 genes, we developed a nomogram for HCC. The high- and low-risk groups were found to have distinct immune characteristics and response to drugs. Unlike CD8 T cells, M0 and M2 macrophages were found to be highly infiltrated in the TME of the high-risk subgroup. High levels of SPGs were found to be a good indicator of response to immunotherapy. In cell function experiments, SMPD2 and CSTA were found to enhance survival and migration of Huh7 cells, while silencing these genes increased the sensitivity of Huh7 cells to lapatinib.ConclusionThe study presents a six-gene signature and a nomogram that can aid clinicians in choosing personalized treatments for HCC patients. Furthermore, it uncovers the connection between sphingolipid-related genes and the immune microenvironment, offering a novel approach for immunotherapy. By focusing on crucial sphingolipid genes like SMPD2 and CSTA, the efficacy of anti-tumor therapy can be increased in HCC cells.

Project description:BackgroundAs essential components of cycle growth, the cell division cycle-associated family genes (CDCAs) have crucial roles in tumor development and progression, especially in hepatocellular carcinoma (HCC). However, due to the tumor heterogeneity of HCC, little is known about the methylation variability of CDCAs in mediating phenotypic changes (e.g., immune infiltrates) in HCC. Presently, we aim to comprehensively explore the expression and prognosis of CDCAs methylation with regard to immune infiltrates of HCC.MethodsWe first identified the correlating differentially expressed genes (co-DEGs) among 19 different types of cancer cohorts (a total of 7,783 patients) and then constructed the weighted gene co-expressed and co-methylated networks. Applying the clustering analysis, significant modules of DEGs including CDCAs were selected and their functional bioinformatics analyses were performed. Besides, using DiseaseMeth and TIMER, the correlation between the methylation levels of CDCAs and tumor immune infiltrates was also analyzed. In final, to assess the influence of CDCAs methylation on clinical prognosis, Kaplan-Meier and Cox regression analysis were carried out.ResultA total of 473 co-DEGs are successfully identified, while seven genes of CDCAs (CDCA1-3 and CDCA5-8) have significant over-expression in HCC. Co-expressed and co-methylated networks reveal the strong positive correlations in mRNA expression and methylation levels of CDCAs. Besides, the biological enrichment analysis of CDCAs demonstrates that they are significantly related to the immune function regulation of infiltrating immune cells in HCC. Also, the methylation analysis of CDCAs depicts the strong association with the tumor immunogenicity, i.e., low-methylation of CDCA1, CDCA2, and CDCA8 dramatically reduced the immune infiltrate levels of T cells and cytotoxic lymphocytes. Additionally, CDCA1-6 and CDCA8 with low-methylation levels significantly deteriorate the overall survival of patients in HCC.ConclusionsThe co-expressed and co-methylated gene networks of CDCAs show a powerful association with immune function regulation. And the methylation levels of CDCAs suggesting the prognostic value and infiltrating immune differences could be a novel and predictive biomarker for the response of immunotherapy.

Dataset Information

Immune Cytolytic Activity for Comprehensive Understanding of Immune Landscape in Hepatocellular Carcinoma.

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Immune Cytolytic Activity for Comprehensive Understanding of Immune Landscape in Hepatocellular Carcinoma.

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