The Role of TLR4 in the Immunotherapy of Hepatocellular Carcinoma: Can We Teach an Old Dog New Tricks?

Papadakos, Stavros P.; Arvanitakis, Konstantinos; Stergiou, Ioanna Ε.; Lekakis, Vasileios; Davakis, Spyridon; Christodoulou, Maria-Ioanna; Theocharis, Stamatios

doi:10.3390/cancers15102795

Cited by 16 publications

(24 citation statements)

References 175 publications

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“…The toll-like receptor (TLR) pathway plays a crucial function in the activation of the host immune response by intestinal microorganisms (Kayama et al, 2020). Gut microbes and their metabolite transport, including LPS and bacterial DNA, can effectively activate the immune response through the activation of TLR, which in turn causes liver injury, and the degree of increase in the plasma level of LPS in patients with AIH is significantly correlated with the severity of AIH (Papadakos et al, 2023;Verma et al, 2023).…”

Section: Gut Microbes and Their Metabolite Transportmentioning

confidence: 99%

The significance of gut microbiota in the etiology of autoimmune hepatitis: a narrative review

Sun,

Zhu,

Zhu

et al. 2024

Front. Cell. Infect. Microbiol.

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Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver that is mediated by autoimmunity and has complex pathogenesis. Its prevalence has increased globally. Since the liver is the first organ to be exposed to harmful substances, such as gut-derived intestinal microbiota and its metabolites, gut health is closely related to liver health, and the “liver-gut axis” allows abnormalities in the gut microbiota to influence the development of liver-related diseases such as AIH. Changes in the composition of the intestinal microbiota and its resultant disruption of the intestinal barrier and microbial transport are involved in multiple ways in the disruption of immune homeostasis and inflammation, thereby influencing the development of AIH. In terms of the mechanisms involved in immune, the gut microbiota or its metabolites, which is decreased in secondary bile acids, short-chain fatty acids (SCFAs), and polyamines, and increased in lipopolysaccharide (LPS), branched-chain amino acids (BCAA), tryptophan metabolite, amino acid, and bile acid, can disrupt immune homeostasis by activating various immune cells and immune-related signaling pathways, resulting in aberrant activation of the immune system. Clarifying this mechanism has significant clinical implications for the treatment of AIH with drugs that target intestinal microbiota and related signaling pathways. Therefore, this narrative review summarizes the progress in exploring the involvement of gut microbiota in the pathogenesis of AIH, with the aim of helping to improve the precise targeting of therapeutic treatments against AIH for the benefit of clinical AIH treatment.

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Section: Gut Microbes and Their Metabolite Transportmentioning

confidence: 99%

The significance of gut microbiota in the etiology of autoimmune hepatitis: a narrative review

Sun,

Zhu,

Zhu

et al. 2024

Front. Cell. Infect. Microbiol.

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“…The stimulated immune response plays an important role in sustaining DNA damage and supporting genomic instability that eventually leads to hepatocyte neoplastic transformation, leading to HCC development [ 227 ]. In recent years, growing evidence has suggested a more complex role for TLR4 in HCC progression, with several aspects to be considered in metastasis promotion, drug resistance, and angiogenesis support [ 228 ]. There is evidence, in HCC, of TRL4 involvement in the facilitated recruitment of T-regs to the tumor site, along with metastasis promotion through its interaction with macrophages [ 229 ].…”

Section: Review Of Established and Novel Potential Targets In Hccmentioning

confidence: 99%

Hepatocellular Carcinoma: Old and Emerging Therapeutic Targets

Pessino,

Scotti,

Maggi

2024

Cancers

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Liver cancer, predominantly hepatocellular carcinoma (HCC), globally ranks sixth in incidence and third in cancer-related deaths. HCC risk factors include non-viral hepatitis, alcohol abuse, environmental exposures, and genetic factors. No specific genetic alterations are unequivocally linked to HCC tumorigenesis. Current standard therapies include surgical options, systemic chemotherapy, and kinase inhibitors, like sorafenib and regorafenib. Immunotherapy, targeting immune checkpoints, represents a promising avenue. FDA-approved checkpoint inhibitors, such as atezolizumab and pembrolizumab, show efficacy, and combination therapies enhance clinical responses. Despite this, the treatment of hepatocellular carcinoma (HCC) remains a challenge, as the complex tumor ecosystem and the immunosuppressive microenvironment associated with it hamper the efficacy of the available therapeutic approaches. This review explores current and advanced approaches to treat HCC, considering both known and new potential targets, especially derived from proteomic analysis, which is today considered as the most promising approach. Exploring novel strategies, this review discusses antibody drug conjugates (ADCs), chimeric antigen receptor T-cell therapy (CAR-T), and engineered antibodies. It then reports a systematic analysis of the main ligand/receptor pairs and molecular pathways reported to be overexpressed in tumor cells, highlighting their potential and limitations. Finally, it discusses TGFβ, one of the most promising targets of the HCC microenvironment.

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“…To maximize the effectiveness of immunotherapy in HCC, it is imperative to identify and develop new targets for immune modulators, thereby augmenting the efficacy of immune checkpoint inhibitors (ICIs). For instance, targeting Toll-like receptor 4 (TLR4) holds potential, given its significant role in orchestrating the immune response against HCC cells [ 183 ]. Similarly, activation of the NLRP3 inflammasome has demonstrated the ability to suppress HCC growth in murine xenograft models [ 184 ].…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications

Park,

Lee,

Lee

et al. 2023

IJMS

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Hepatocellular Carcinoma (HCC) continues to pose a substantial global health challenge due to its high incidence and limited therapeutic options. In recent years, the Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has emerged as a critical signaling cascade in HCC pathogenesis. The review commences with an overview of the JAK/STAT pathway, delving into the dynamic interplay between the JAK/STAT pathway and its numerous upstream activators, such as cytokines and growth factors enriched in pathogenic livers afflicted with chronic inflammation and cirrhosis. This paper also elucidates how the persistent activation of JAK/STAT signaling leads to diverse oncogenic processes during hepatocarcinogenesis, including uncontrolled cell proliferation, evasion of apoptosis, and immune escape. In the context of therapeutic implications, this review summarizes recent advancements in targeting the JAK/STAT pathway for HCC treatment. Preclinical and clinical studies investigating inhibitors and modulators of JAK/STAT signaling are discussed, highlighting their potential in suppressing the deadly disease. The insights presented herein underscore the necessity for continued research into targeting the JAK/STAT signaling pathway as a promising avenue for HCC therapy.

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The Role of TLR4 in the Immunotherapy of Hepatocellular Carcinoma: Can We Teach an Old Dog New Tricks?

Cited by 16 publications

References 175 publications

The significance of gut microbiota in the etiology of autoimmune hepatitis: a narrative review

The significance of gut microbiota in the etiology of autoimmune hepatitis: a narrative review

Hepatocellular Carcinoma: Old and Emerging Therapeutic Targets

Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications

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