Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver

Tang, WM; Zhou, Jingying; Yang, Weiqin; Feng, Yuanming; Wu, Haoran; Mok, Myth T.S.; Zhang, Lingyun; Liang, Zhixian; Liu, Xiaoyu; Xiong, Zhewen; Zeng, Xuezhen; Wang, Jing; Lu, Jiahuan; Li, Jingqing; Sun, Hanyong; Tian, Xiaoyu; Yeung, Philip Chun; Hou, Yong; Lee, Heung Man; Lam, Candice C.; Leung, Howard H. W.; Chan, Anthony W.H.; To, Ka‐Fai; Wong, John; Lai, Paul Bo San; K, Ng; Wong, Sunny Kit-Man; Wong, Vincent Wai‐Sun; Kong, Alice Pik‐Shan; Sung, Joseph J.Y.; Cheng, Alfred Sze‐Lok

doi:10.1038/s41423-022-00872-3

Cited by 45 publications

(40 citation statements)

References 63 publications

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“…Among the metabolic imbalances occurring in NASH, aberrant cholesterol metabolism represents a typical hallmark with serious consequences for the disease evolution. In a recent study, Tang et al [ 119 ] have reported that cholesterol accumulation within NKT cells induces lipid peroxidation leading to their functional impairment and favours orthotopic tumour growth in obese mice. In the same settings, the cytolytic functions of hepatic NKT cells are restored by treating mice with statins to normalize plasma cholesterol levels [ 120 ].…”

Section: Immunomodulating Mechanisms Underlying Nash-related Hccmentioning

confidence: 99%

Inflammatory processes involved in NASH-related hepatocellular carcinoma

et al. 2023

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Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. In the recent years nonalcoholic fatty liver disease (NAFLD) is becoming a growing cause of HCCs and the incidence of NAFLD-related HCCs is expected to further dramatically increase by the next decade. Chronic inflammation is regarded as the driving force of NAFLD progression and a key factor in hepatic carcinogenesis. Hepatic inflammation in NAFLD results from the persistent stimulation of innate immunity in response to hepatocellular injury and gut dysbiosis as well as by the activation of adaptive immunity. However, the relative roles of innate and adaptive immunity in the processes leading to HCC are still incompletely characterized. This is due to the complex interplay between different liver cell populations, which is also strongly influenced by gut-derived bacterial products, metabolic/nutritional signals. Furthermore, carcinogenic mechanisms in NAFLD/NASH appear to involve the activation of signals mediated by hypoxia inducible factors. This review discusses recent data regarding the contribution of different inflammatory cells to NAFLD-related HCC and their possible impact on patient response to current treatments.

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Section: Immunomodulating Mechanisms Underlying Nash-related Hccmentioning

confidence: 99%

Inflammatory processes involved in NASH-related hepatocellular carcinoma

et al. 2023

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“…Along with this, the HCC immune microenvironment sees an enrichment of CD8 + and CD4 + T-lymphocytes showing an exhausted phenotype following the chronic antigen stimulation [ 27 , 48 , 49 ]. Furthermore, metabolic derangements occurring in HCC lower the fraction of CD4 + T-helper cells [ 50 ] and increase the amount of dysfunctional natural killer (NK) and NKT cells, favoring the loss of cancer immunosurveillance [ 51 , 52 ]. In parallel, plasma cell accumulation within the HCC microenvironment dismantles antitumor immunity by producing inhibitory mediators such as PD-L1 and IL-10 and inhibiting CD8 + T-cell activation [ 53 ].…”

Section: The Immune Landscape Of Hccmentioning

confidence: 99%

Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses

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et al. 2023

IJMS

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Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading causes of cancer-related mortality worldwide and whose incidence varies according to geographical area and ethnicity. Metabolic rewiring was recently introduced as an emerging hallmark able to affect tumor progression by modulating cancer cell behavior and immune responses. This review focuses on the recent studies examining HCC’s metabolic traits, with particular reference to the alterations of glucose, fatty acid and amino acid metabolism, the three major metabolic changes that have gained attention in the field of HCC. After delivering a panoramic picture of the peculiar immune landscape of HCC, this review will also discuss how the metabolic reprogramming of liver cancer cells can affect, directly or indirectly, the microenvironment and the function of the different immune cell populations, eventually favoring the tumor escape from immunosurveillance.

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“…Obesity has been identified to promote most cancer progression, including breast cancer [ 47 , 48 ], HCC [ 49 , 50 ], and pancreatic ductal adenocarcinoma (PDAC) [ 51 , 52 ]. Insulin resistance, adipose inflammation, and tumor-promoting growth factors such as fibroblast growth factor 1 (FGF1) are closely associated with most cancer progression [ 47 ].…”

Section: Obesity Its Comorbidities and Associated Factorsmentioning

confidence: 99%

“…In addition, obesity can impair anti-tumor immunity. For example, obesity-induced hepatic cholesterol accumulation selectively represses the anti-tumor effects of natural killer T (NKT) cells during diet-induced, NAFLD-related HCC [ 50 ]. A molecular study further shows that sterol regulatory element-binding protein 2 (SREBP2)-mediated excessive accumulation of cholesterol in hepatocytes causes lipid peroxide accumulation in NKT cells to reduce their cytotoxicity to tumor cells [ 50 ].…”

Section: Obesity Its Comorbidities and Associated Factorsmentioning

confidence: 99%

The Related Metabolic Diseases and Treatments of Obesity

2022

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Obesity is a chronic disease characterized by the abnormal or excessive accumulation of body fat, affecting more than 1 billion people worldwide. Obesity is commonly associated with other metabolic disorders, such as type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular diseases, chronic kidney disease, and cancers. Factors such as a sedentary lifestyle, overnutrition, socioeconomic status, and other environmental and genetic conditions can cause obesity. Many molecules and signaling pathways are involved in the pathogenesis of obesity, such as nuclear factor (NF)-κB, Toll-like receptors (TLRs), adhesion molecules, G protein-coupled receptors (GPCRs), programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1), and sirtuin 1 (SIRT1). Commonly used strategies of obesity management and treatment include exercise and dietary change or restriction for the early stage of obesity, bariatric surgery for server obesity, and Food and Drug Administration (FDA)-approved medicines such as semaglutide and liraglutide that can be used as monotherapy or as a synergistic treatment. In addition, psychological management, especially for patients with obesity and distress, is a good option. Gut microbiota plays an important role in obesity and its comorbidities, and gut microbial reprogramming by fecal microbiota transplantation (FMT), probiotics, prebiotics, or synbiotics shows promising potential in obesity and metabolic syndrome. Many clinical trials are ongoing to evaluate the therapeutic effects of different treatments. Currently, prevention and early treatment of obesity are the best options to prevent its progression to many comorbidities.

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Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver

Cited by 45 publications

References 63 publications

Inflammatory processes involved in NASH-related hepatocellular carcinoma

Inflammatory processes involved in NASH-related hepatocellular carcinoma

Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses

The Related Metabolic Diseases and Treatments of Obesity

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