Metabolic reprogramming of immune cells: Shaping the tumor microenvironment in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies. Recent studies reveal that tumor microenvironment (TME) components significantly affect HCC growth and progression, particularly the infiltrating stromal and immune cells. Thus, mining of TME-related biomarkers is crucial to improve the survival of patients with HCC. Public access of The Cancer Genome Atlas (TCGA) database allows convenient performance of gene expression-based analysis of big data, which contributes to the exploration of potential association between genes and prognosis of a variety of malignancies, including HCC. The “Estimation of STromal and Immune cells in MAlignant Tumors using Expression data” algorithm renders the quantification of the stromal and immune components in TME possible by calculating the stromal and immune scores. Differentially expressed genes (DEGs) were screened by dividing the HCC cohort of TCGA database into high- and low-score groups according to stromal and immune scores. Further analyses of functional enrichment and protein-protein interaction networks show that the DEGs are mainly involved in immune response, cell adhesion, and extracellular matrix. Finally, seven DEGs have significant association with HCC poor outcomes. These genes contain FABP3, GALNT5, GPR84, ITGB6, MYEOV, PLEKHS1, and STRA6 and may be candidate biomarkers for HCC prognosis.

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Metabolic Reprogramming Induces Immune Cell Dysfunction in the Tumor Microenvironment of Multiple Myeloma

Frontiers in Oncology ◽

10.3389/fonc.2020.591342 ◽

2021 ◽

Vol 10 ◽

Author(s):

Shaojie Wu ◽

Huixian Kuang ◽

Jin Ke ◽

Manfei Pi ◽

Dong-Hua Yang

Keyword(s):

Multiple Myeloma ◽

Tumor Microenvironment ◽

Cancer Progression ◽

Immune Cells ◽

Immune Cell ◽

Metabolic Reprogramming ◽

Metabolic Phenotype ◽

Cell Dysfunction ◽

Promising Therapeutic Approach ◽

Tumor Survival

Tumor cells rewire metabolism to meet their increased nutritional demands, allowing the maintenance of tumor survival, proliferation, and expansion. Enhancement of glycolysis and glutaminolysis is identified in most, if not all cancers, including multiple myeloma (MM), which interacts with a hypoxic, acidic, and nutritionally deficient tumor microenvironment (TME). In this review, we discuss the metabolic changes including generation, depletion or accumulation of metabolites and signaling pathways, as well as their relationship with the TME in MM cells. Moreover, we describe the crosstalk among metabolism, TME, and changing function of immune cells during cancer progression. The overlapping metabolic phenotype between MM and immune cells is discussed. In this sense, targeting metabolism of MM cells is a promising therapeutic approach. We propose that it is important to define the metabolic signatures that may regulate the function of immune cells in TME in order to improve the response to immunotherapy.

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A Novel Lactate Metabolism-Related Gene Signature for Predicting Clinical Outcome and Tumor Microenvironment in Hepatocellular Carcinoma

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.801959 ◽

2022 ◽

Vol 9 ◽

Author(s):

Yue Li ◽

Huanye Mo ◽

Shengli Wu ◽

Xin Liu ◽

Kangsheng Tu

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Tumor Microenvironment ◽

External Validation ◽

Gene Signature ◽

Metabolic Reprogramming ◽

Lactate Metabolism ◽

Related Gene ◽

High Group ◽

Cox Regression Analysis

Hepatocellular carcinoma (HCC) is the main subtype of primary liver cancer with high malignancy and poor prognosis. Metabolic reprogramming is a hallmark of cancer and has great importance on the tumor microenvironment (TME). As an abundant metabolite, lactate plays a crucial role in cancer progression and the immunosuppressive TME. Nonetheless, the potential roles of lactate in HCC remain unclear. In this study, we downloaded transcriptomic data of HCC patients with corresponding clinical information from the TCGA and ICGC portals. The TCGA-HCC dataset used as the training cohort, while the ICGC-LIRI-JP dataset was served as an external validation cohort. Cox regression analysis and the LASSO regression model were combined to construct the lactate metabolism-related gene signature (LMRGS). Then, we assessed the clinical significance of LMRGS in HCC. Besides, enriched molecular functions, tumor mutation burden (TMB), infiltrating immune cells, and immune checkpoint were comprehensively analyzed in different LMRGS subgroups. In total, 66 differentially expressed lactate metabolism-related genes (LMRGs) were screened. The functions of LMRGs were mainly enriched in mitochondrial activity and metabolic processes. The LMRGS comprised of six key LMRGs (FKTN, PDSS1, PET117, PUS1, RARS1, and RNASEH1) had significant clinical value for independently predicting the prognosis of HCC patients. The overall survival and median survival of patients in the LMRGS-high group were significantly shorter than in the LMRGS-low group. In addition, there were differences in TMB between the two LMRGS subgroups. The probability of genetic mutations was higher in the LMRGS-high group. Most importantly, the LMRGS reflected the TME characteristics. In the LMRGS-high group, the immune microenvironment presented a suppressed state, accompanied by more inhibitory immune cell infiltration, including follicular helper T cells and regulatory T cells. Additionally, the expression of inhibitory checkpoint molecules was much higher in the LMRGS-high group. Our study suggested that the LMRGS was a robust biomarker to predict the clinical outcomes and evaluate the TME of patients with HCC.

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Abstract 1942: AGX73 is an effective treatment for hepatocellular carcinoma (HCC) by selective inhibition of immunokinases that play crucial roles in the crosstalk between cancer and immune cells in the tumor microenvironment

10.1158/1538-7445.am2020-1942 ◽

2020 ◽

Author(s):

Francis Y.F. Lee ◽

Wenlian Wu ◽

Zhiqiang Yang ◽

John Tan

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment ◽

Effective Treatment ◽

Immune Cells ◽

Selective Inhibition

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Immunometabolism in the Tumor Microenvironment

Annual Review of Cancer Biology ◽

10.1146/annurev-cancerbio-030518-055817 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Dominic G. Roy ◽

Irem Kaymak ◽

Kelsey S. Williams ◽

Eric H. Ma ◽

Russell G. Jones

Keyword(s):

Tumor Microenvironment ◽

Immune Cells ◽

Cancer Biology ◽

Antitumor Immunity ◽

Immune Cell ◽

Metabolic Reprogramming ◽

Proper Function ◽

Annual Review ◽

Publication Date ◽

And Function

Advances in immunotherapy have underscored the importance of antitumor immune responses in controlling cancer. However, the tumor microenvironment (TME) imposes several obstacles to the proper function of immune cells, including a metabolically challenging and immunosuppressive microenvironment. The increased metabolic activity of tumor cells can lead to the depletion of key nutrients required by immune cells and the accumulation of byproducts that hamper antitumor immunity. Furthermore, the presence of suppressive immune cells, such as regulatory T cells and myeloid-derived suppressor cells, and the expression of immune inhibitory receptors can negatively impact immune cell metabolism and function. This review summarizes the metabolic reprogramming that is characteristic of various immune cell subsets, discusses how the metabolism and function of immune cells is shaped by the TME, and highlights how therapeutic interventions aimed at improving the metabolic fitness of immune cells and alleviating the metabolic constraints in the TME can boost antitumor immunity. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Indoleamine 2,3-dioxygenase regulates anti-tumor immunity in lung cancer by metabolic reprogramming of immune cells in the tumor microenvironment

Oncotarget ◽

10.18632/oncotarget.12249 ◽

2016 ◽

Vol 7 (46) ◽

pp. 75407-75424 ◽

Cited By ~ 29

Author(s):

Cara C. Schafer ◽

Yong Wang ◽

Kenneth P. Hough ◽

Anandi Sawant ◽

Stefan C. Grant ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Microenvironment ◽

Tumor Immunity ◽

Immune Cells ◽

Metabolic Reprogramming ◽

Indoleamine 2,3 Dioxygenase

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Cancer cell metabolic reprogramming: a keystone for the response to immunotherapy

Cell Death and Disease ◽

10.1038/s41419-020-03175-5 ◽

2020 ◽

Vol 11 (11) ◽

Cited By ~ 1

Author(s):

Michaël Cerezo ◽

Stéphane Rocchi

Keyword(s):

Tumor Microenvironment ◽

Immune Cells ◽

Metabolic Pathways ◽

Immune Checkpoint Inhibitors ◽

Antitumor Immunity ◽

Checkpoint Inhibitors ◽

Metabolic Reprogramming ◽

Limited Resources ◽

Antitumor Response ◽

Secondary Resistance

Abstract By targeting the tumor microenvironment to stimulate antitumor immunity, immunotherapies have revolutionized cancer treatment. However, many patients do not respond initially or develop secondary resistance. Based on the limited resources in the tumor microenvironment and competition between tumor and immune cells, the field of immune metabolism has produced extensive knowledge showing that targeting metabolism could help to modulate antitumor immunity. However, among all the different potentially targetable metabolic pathways, it remains unclear which have more potential to overcome resistance to immune checkpoint inhibitors. Here, we explore metabolic reprogramming in cancer cells, which might inhibit antitumor immunity, and strategies that can be used to favor the antitumor response.

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Identification of Novel Tumor Microenvironment-Related Long Noncoding RNAs to Determine the Prognosis and Response to Immunotherapy of Hepatocellular Carcinoma Patients

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.781307 ◽

2021 ◽

Vol 8 ◽

Author(s):

Shenglan Huang ◽

Jian Zhang ◽

Xiaolan Lai ◽

Lingling Zhuang ◽

Jianbing Wu

Keyword(s):

Hepatocellular Carcinoma ◽

High Risk ◽

Tumor Microenvironment ◽

Immune Cells ◽

Risk Model ◽

Cox Regression ◽

Risk Group ◽

Low Risk ◽

Kaplan Meier ◽

Treatment Responses

Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with poor prognosis. The tumor microenvironment (TME) plays a vital role in HCC progression. Thus, this research was designed to analyze the correlation between the TME and the prognosis of HCC patients and to construct a TME-related long noncoding RNA (lncRNA) signature to determine HCC patients’ prognosis and response to immunotherapy.Methods: We assessed the stromal–immune–estimate scores within the HCC microenvironment using the ESTIMATE (Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data) algorithm based on The Cancer Genome Atlas database, and their associations with survival and clinicopathological parameters were also analyzed. Thereafter, differentially expressed lncRNAs were filtered out according to the immune and stromal scores. Cox regression analysis was performed to build a TME-related lncRNA risk signature. Kaplan–Meier analysis was used to explore the prognostic value of the risk signature. Furthermore, we explored the biological functions and immune microenvironment features in the high- and low-risk groups. Lastly, we probed the association of the risk model with treatment responses to immune checkpoint inhibitors (ICIs) in HCC.Results: The stromal, immune, and estimate scores were obtained utilizing the ESTIMATE algorithm for patients with HCC. Kaplan–Meier analysis showed that high scores were significantly correlated with better prognosis in HCC patients. Six TME-related lncRNAs were screened to construct the prognostic model. The Kaplan–Meier curves suggested that HCC patients with low risk had better prognosis than those with high risk. Receiver operating characteristic (ROC) curve and Cox regression analyses indicated that the risk model could predict HCC survival exactly and independently. Functional enrichment analysis revealed that some tumor- and immune-related pathways were activated in the high-risk group. We also revealed that some immune cells, which were important in enhancing immune responses toward cancer, were significantly increased in the low-risk group. In addition, there was a close correlation between ICIs and the risk signature, which can be used to predict the treatment responses of HCC patients.Conclusion: We analyzed the influence of the stromal, immune, and estimate scores on the prognosis of HCC patients. A novel TME-related lncRNA risk model was established, which could be effectively applied as an independent prognostic biomarker and predictor of ICIs for HCC patients.

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Current Perspectives on B Lymphocytes in the Immunobiology of Hepatocellular Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.647854 ◽

2021 ◽

Vol 11 ◽

Author(s):

Miaomiao Qin ◽

Danping Wang ◽

Yijiao Fang ◽

Zhiying Zheng ◽

Xinyang Liu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment ◽

T Lymphocytes ◽

Cell Therapy ◽

B Cell ◽

B Lymphocytes ◽

Immune Cells ◽

Cell Biology ◽

Therapy Strategy ◽

The Way

Immune cells infiltrating tumors are capable of significantly impacting carcinogenesis through cancer promotion and anticancer responses. There are many aspects of hepatocellular carcinoma (HCC) related T lymphocytes that are undergoing extensive studies, whereas the effect exerted by B lymphocytes remains a less researched area. In this study, the latest research on the effect of B lymphocytes as they infiltrate tumors in relation to HCC is presented. Their prognosis-related importance is analyzed, along with their function in the tumor microenvironment (TME), as well as the way that B cell biology can be employed to help create a B cell therapy strategy for HCC.

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MicroRNA-Mediated Metabolic Shaping of the Tumor Microenvironment

Cancers ◽

10.3390/cancers13010127 ◽

2021 ◽

Vol 13 (1) ◽

pp. 127

Author(s):

Federico Virga ◽

Lorena Quirico ◽

Stefania Cucinelli ◽

Massimiliano Mazzone ◽

Daniela Taverna ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

Cancer Cells ◽

Immune Cells ◽

Metabolic Reprogramming ◽

Stromal Fibroblasts ◽

Metabolic Alterations ◽

Cell Functions ◽

Cancer Management ◽

Mrna Targets

The metabolism of cancer cells is generally very different from what is found in normal counterparts. However, in a tumor mass, the continuous crosstalk and competition for nutrients and oxygen among different cells lead to metabolic alterations, not only in cancer cells, but also in the different stromal and immune cells of the tumor microenvironment (TME), which are highly relevant for tumor progression. MicroRNAs (miRs) are small non-coding RNAs that silence their mRNA targets post-transcriptionally and are involved in numerous physiological cell functions as well as in the adaptation to stress situations. Importantly, miRs can also be released via extracellular vesicles (EVs) and, consequently, take part in the bidirectional communication between tumor and surrounding cells under stress conditions. Certain miRs are abundantly expressed in stromal and immune cells where they can regulate various metabolic pathways by directly suppressing enzymes or transporters as well as by controlling important regulators (such as transcription factors) of metabolic processes. In this review, we discuss how miRs can induce metabolic reprogramming in stromal (fibroblasts and adipocytes) and immune (macrophages and T cells) cells and, in turn, how the biology of the different cells present in the TME is able to change. Finally, we debate the rebound of miR-dependent metabolic alterations on tumor progression and their implications for cancer management.

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