Dataset Information

Key Genes Associated with Tumor-Infiltrating Non-regulatory CD4- and CD8-Positive T Cells in Microenvironment of Hepatocellular Carcinoma.

ABSTRACT: The immune microenvironment in hepatocellular carcinoma (HCC), especially T-cell infiltration, plays a key role in the prognosis and drug sensitivity of HCC. Our study aimed to analyze genes related to non-regulatory CD4⁺ and CD8⁺ T cell in HCC. Data of HCC samples were downloaded from The Cancer Genome Atlas (TCGA) database. According to stromal and immune score retrieved by Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithm, differentiated expressed genes (DEGs) between high and low stromal/immune scoring groups were collected. Using Cibersort algorithm, abundance of immune cells was calculated and genes related with CD4⁺ and CD8⁺ T cells were selected. Protein-protein interaction (PPI) networks and networks of microRNA (miRNA)-target gene interactions were illustrated, in which CD4⁺ and CD8⁺ T cell-related core genes were selected. Finally, Cox regression test and Kaplan-Meier (K-M) survival analysis were conducted. Totally, 1579 DEGs were identified, where 103 genes and 407 genes related with CD4⁺ and CD8⁺ T cell were selected, respectively. Each of 30 core genes related to CD4⁺ T cells and CD8⁺ T cells were selected by PPI network. Four genes each related with the two types of T cells had a significant impact on prognosis of HCC patients. Amongst, KLRB1 and IL18RAP were final two genes related to both two kinds of T cells and associated with overall survival of the HCC patients.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC9470630 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Key Genes Associated with Tumor-Infiltrating Non-regulatory CD4- and CD8-Positive T Cells in Microenvironment of Hepatocellular Carcinoma.

Zhao Zijun Z Wang Chaonan C Chu Peishan P Lu Xin X

Biochemical genetics 20220129 5

The immune microenvironment in hepatocellular carcinoma (HCC), especially T-cell infiltration, plays a key role in the prognosis and drug sensitivity of HCC. Our study aimed to analyze genes related to non-regulatory CD4<sup>+</sup> and CD8<sup>+</sup> T cell in HCC. Data of HCC samples were downloaded from The Cancer Genome Atlas (TCGA) database. According to stromal and immune score retrieved by Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) ...[more]

PMID: 35092558

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Project description:BACKGROUND AND AIMS:Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4-1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor-infiltrating CD8+ T cells (CD8+ tumor-infiltrating lymphocytes [TILs]) and its association with distinct T-cell activation features among exhausted CD8+ TILs in hepatocellular carcinoma (HCC). APPROACH AND RESULTS:Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA-sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4-1BB was most prominently expressed on CD8+ TILs. 4-1BB expression was almost exclusively detected on CD8+ T cells in the tumor-especially on programmed death 1 (PD-1)high cells and not PD-1int and PD-1neg cells. Compared to PD-1int and 4-1BBneg PD-1high CD8+ TILs, 4-1BBpos PD-1high CD8+ TILs exhibited higher levels of tumor reactivity and T-cell activation markers and significant enrichment for T-cell activation gene signatures. Per-patient analysis revealed positive correlations between percentages of 4-1BBpos cells among CD8+ TILs and levels of parameters of tumor reactivity and T-cell activation. Among highly exhausted PD-1high CD8+ TILs, 4-1BBpos cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4-1BB-related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4-1BB agonistic antibodies enhanced the function of CD8+ TILs and further enhanced the anti-PD-1-mediated reinvigoration of CD8+ TILs, especially in cases showing high levels of T-cell activation. CONCLUSION:4-1BB expression on CD8+ TILs represents a distinct activation state among highly exhausted CD8+ T cells in HCC. 4-1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T-cell activation.

Project description:Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the third leading cause of tumor-related mortality worldwide. In recent years, the emergency of immune checkpoint inhibitor (ICI) has revolutionized the management of HCC. Especially, the combination of atezolizumab (anti-PD1) and bevacizumab (anti-VEGF) has been approved by the FDA as the first-line treatment for advanced HCC. Despite great breakthrough in systemic therapy, HCC continues to portend a poor prognosis owing to drug resistance and frequent recurrence. The tumor microenvironment (TME) of HCC is a complex and structured mixture characterized by abnormal angiogenesis, chronic inflammation, and dysregulated extracellular matrix (ECM) remodeling, collectively contributing to the immunosuppressive milieu that in turn prompts HCC proliferation, invasion, and metastasis. The tumor microenvironment coexists and interacts with various immune cells to maintain the development of HCC. It is widely accepted that a dysfunctional tumor-immune ecosystem can lead to the failure of immune surveillance. The immunosuppressive TME is an external cause for immune evasion in HCC consisting of 1) immunosuppressive cells; 2) co-inhibitory signals; 3) soluble cytokines and signaling cascades; 4) metabolically hostile tumor microenvironment; 5) the gut microbiota that affects the immune microenvironment. Importantly, the effectiveness of immunotherapy largely depends on the tumor immune microenvironment (TIME). Also, the gut microbiota and metabolism profoundly affect the immune microenvironment. Understanding how TME affects HCC development and progression will contribute to better preventing HCC-specific immune evasion and overcoming resistance to already developed therapies. In this review, we mainly introduce immune evasion of HCC underlying the role of immune microenvironment, describe the dynamic interaction of immune microenvironment with dysfunctional metabolism and the gut microbiome, and propose therapeutic strategies to manipulate the TME in favor of more effective immunotherapy.

Dataset Information

Key Genes Associated with Tumor-Infiltrating Non-regulatory CD4- and CD8-Positive T Cells in Microenvironment of Hepatocellular Carcinoma.

Publications

Key Genes Associated with Tumor-Infiltrating Non-regulatory CD4- and CD8-Positive T Cells in Microenvironment of Hepatocellular Carcinoma.

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