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Myeloid-derived suppressor cell infiltration is associated with a poor prognosis in patients with hepatocellular carcinoma.

ABSTRACT: The clinicopathological features of myeloid-derived suppressor cell (MDSC) and CD8⁺ T-cell infiltration in hepatocellular carcinoma (HCC) are poorly understood. The present study examined MDSC and CD8⁺ T-cell infiltration in surgically resected primary HCC specimens and investigated the association of MDSC and CD8⁺ T-cell infiltration with clinicopathological features and patient outcomes. Using a database of 466 patients who underwent hepatic resection for HCC, immunohistochemical staining of CD33 (an MDSC marker) and CD8 was performed. High infiltration of MDSCs within the tumor was observed in patients with a poorer Barcelona Clinic Liver Cancer stage, larger tumor size, more poorly differentiated HCC, and greater presence of portal venous thrombosis, microscopic vascular thrombosis and macroscopic intrahepatic metastasis. MDSC infiltration and CD8⁺ T-cell infiltration were independent predictors of recurrence-free survival and overall survival, respectively. Stratification based on the MDSC and CD8⁺ T-cell status of the tumors was also associated with recurrence-free survival (10 year-recurrence-free survival; MDSC^highCD8⁺ T-cell^Low, 3.68%; others, 25.7%) and overall survival (10 year-overall survival; MDSC^highCD8⁺ T-cell^Low, 12.0%; others, 56.7%). In conclusion, the present large cohort study revealed that high MDSC infiltration was associated with a poor clinical outcome in patients with HCC. Furthermore, the combination of the MDSC and tumor-infiltrating CD8⁺ T-cell status enabled further classification of patients based on their outcomes.

SUBMITTER: Tomiyama T

PROVIDER: S-EPMC8822414 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Myeloid-derived suppressor cell infiltration is associated with a poor prognosis in patients with hepatocellular carcinoma.

Tomiyama Takahiro T Itoh Shinji S Iseda Norifumi N Toshida Katuya K Morinaga Akinari A Yugawa Kyohei K Fujimoto Yukiko Kosai YK Tomino Takahiro T Kurihara Takeshi T Nagao Yoshihiro Y Morita Kazutoyo K Harada Noboru N Kohashi Kenichi K Oda Yoshinao Y Mori Masaki M Yoshizumi Tomoharu T

Oncology letters 20220127 3

The clinicopathological features of myeloid-derived suppressor cell (MDSC) and CD8+ T-cell infiltration in hepatocellular carcinoma (HCC) are poorly understood. The present study examined MDSC and CD8+ T-cell infiltration in surgically resected primary HCC specimens and investigated the association of MDSC and CD8+ T-cell infiltration with clinicopathological features and patient outcomes. Using a database of 466 patients who underwent hepatic resection for HCC, ...[more]

PMID: 35154424

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Project description:Objective: This study aimed to validate FANCI as a potential marker for both prognosis and therapy in liver hepatocellular carcinoma. Method: FANCI expression data were acquired from GEPIA, HPA, TCGA, and GEO databases. The impact of clinicopathological features was analyzed by UALCAN. The prognosis of Liver Hepatocellular Carcinoma (LIHC) patients with highly expressed FANCI was constructed utilizing Kaplan-Meier Plotter. GEO2R was employed to identify differentially expressed genes (DEGs). Metascape was used to analyze functional pathways correlations. Protein-Protein interaction (PPI) networks were generated by Cytoscape. Furthermore, molecular complex detection (MCODE) was utilized to recognize Hub genes, which were selected to establish a prognostic model. Lastly, the relationship between FANCI and immune cell infiltration in LIHC was examined. Results: Compared to adjacent tissues, FANCI expression levels were significantly higher in LIHC tissues and were positively correlated to the cancer grade, stage, and prior hepatitis B virus (HBV) infection. High expression of FANCI was found to be associated with poor prognosis in LIHC (HR=1.89, p<0.001). DEGs that were positively correlated with FANCI were involved in various processes, including the cell cycle, VEGF pathway, immune system processes, and biogenesis of ribonucleoproteins. MCM10, TPX2, PRC1, and KIF11 were identified as key genes closely related to FANCI and poor prognosis. A reliable five-variable prognostic model was constructed with strong predictive capability. Lastly, a positive correlation was observed between FANCI expression and tumor-infiltration levels of CD8+ T cells, B cells, regulatory T (Tregs), CD4+ T helper 2 (Th2), and macrophage M2 cells. Conclusion: FANCI may hold promise as a potential biomarker for predicting prognostic outcomes, and a valuable therapeutic target for LIHC patients, with a focus on anti-proliferation, anti-chemoresistance, and combination with immunotherapy.

Project description:BackgroundPreclinical studies and clinical trials have demonstrated that tumor-intrinsic activation of the cell cycle program impedes anticancer immunotherapy. Identification of cell cycle-related biomarkers may provide novel therapeutic targets to augment the efficacy of immunotherapy in hepatocellular carcinoma (HCC).Method and resultsBased on the genes related to cell cycle program, two clusters (Cluster 1 and Cluster 2) were detected in HCC patients via non-negative matrix factorization algorithm. Multivariable-adjusted Cox regression analysis indicated that the cell cycle gene-based classification was a significant prognostic factor for predicting the clinical outcome of HCC patients. Cluster 1 showed shorter overall survival time and progression-free interval time was associated with activated cell cycle program, higher infiltration of myeloid-derived suppressor cells (MDSCs) and less sensitivity to immunotherapy. A three-gene prognostic model, including BIRC5, C8G, and SPP1, was constructed to characterize the cell cycle-based classification of HCC, which had strong robustness and a stable predictive performance. Notably, Birc5 was positively correlated with CD11b expression (a MDSC marker) in HCC tissue. Concordant high expression of Birc5 and intratumor infiltration level of MDSCs were correlated with worse prognosis of HCC patients. In vitro, hepatocellular Birc5 overexpression promoted immunosuppressive CD11b+ CD33+ HLA-DR- MDSC expansion from human peripheral blood mononuclear cells. Genetically modified animal model of liver cancer revealed that Birc5 depletion upregulated the genes related to lymphocyte-mediated immunity, natural killer cell-mediated immunity, interferon-gamma production, T-cell activation, and T-cell-mediated cytotoxicity. These results suggest an immunosuppressive function of Birc5 in HCC.ConclusionBirc5 was a potential biomarker and inducer of intratumor infiltration of MDSCs, which led to T cell exclusion or dysfunction in tumor immune microenvironment, consequently resulting in reduced response to ICIs in HCC.

Project description:PurposeHepatocellular carcinoma (HCC) is one of the most commonly diagnosed digestive cancers and the fourth leading cause of death worldwide. Long noncoding RNAs (lncRNAs) with key roles in HCC development and progression have emerged and are used in the diagnosis and prognostic prediction of HCC. The lncRNA gradually increased during hepatocarcinogenesis (GIHCG) is a novel lncRNA with aberrant expression in many tumors, but its prognostic value and biological role in HCC have not been fully studied. Thus, the aim of this study was to explore the expression pattern and potential biological role of GIHCG in HCC.Patients and methodsThe expression pattern of GIHCG in HCC was analyzed in our HCC cohort and validated in The Cancer Genome Atlas (TCGA) database. To assess the prognostic value of GIHCG, survival analyses and Cox regression analyses were carried out in two HCC cohorts. Functional enrichment analysis was used to predict the gene sets and pathways related to aberrant GIHCG expression. Furthermore, the relationship between GIHCG expression and immune infiltration in HCC was analyzed.ResultsGIHCG was highly expressed in HCC tissues compared with normal liver tissues. In addition, high GIHCG expression was significantly correlated with inferior clinicopathological characteristics and shorter survival times. High GIHCG expression was an independent prognostic factor for overall survival and disease-free survival in the HCC cohort in our center and in the TCGA-LIHC cohort. Hallmark terms such as "G2M checkpoint", "MYC targets" and "DNA repair" were enriched in the GIHCG high-expression groups. High GIHCG expression negatively correlated with the infiltration of memory CD4+ and CD8+ T cells, natural killer cells, macrophages, dendritic cells, neutrophils and monocytes.ConclusionThe findings of our study indicate that GIHCG is a biomarker that can be used to predict the prognosis of HCC patients and is correlated with immune cell infiltration in HCC.

Dataset Information

Myeloid-derived suppressor cell infiltration is associated with a poor prognosis in patients with hepatocellular carcinoma.

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Myeloid-derived suppressor cell infiltration is associated with a poor prognosis in patients with hepatocellular carcinoma.

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