Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma

Yang, Changjie; Qian, Qiwei; Zhao, Yudong; Huang, Bingyuan; Chen, Ruilin; Gong, Qiang; Jiang, Hao; Wang, Chenchen; Lei, Xia; You, Zhengrui; Zhang, Jianjun; Chen, Xiaosong

doi:10.3389/fimmu.2023.1112672

Cited by 9 publications

(3 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After microPET imaging, xenografts were harvested and stored at −80 °C. The frozen tissues were sectioned and stained for FGL1 evaluation using the same procedures as described in the literature . After they were interacting with a primary antibody (Proteintech), the slides were incubated with a biotinylated secondary antibody (Gene Tech), and visualization was performed using peroxidase.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Characterization of a Novel PET Tracer for Noninvasive Evaluation of FGL1 Status in Tumors

Tan,

Ding,

Pan

et al. 2024

Mol. Pharmaceutics

View full text Add to dashboard Cite

Fibrinogen-like protein 1 (FGL1) is a potential novel immune checkpoint target for malignant tumor diagnosis and therapy. Accurate detection of FGL1 levels in tumors via noninvasive PET imaging might be beneficial for managing the disease. To achieve this, multiple FGL1-targeting peptides (FGLP) were designed, and a promising candidate, 68 Ga-NOTA-FGLP2, was identified through a high-throughput screening approach using microPET imaging of 68 Ga-labeled peptides. Subsequent in vitro cell experiments showed that uptake values of 68 Ga-NOTA-FGLP2 in FGL1 positive Huh7 tumor cells were significantly higher than those in FGL1 negative U87 MG tumor cells. Further microPET imaging showed that the Huh7 xenografts were clearly visualized with a favorable contrast. ROI analysis showed that the uptake values of the tracer in Huh7 xenografts were 2.63 ± 0.07% ID/g at 30 min p.i.. After treatment with an excess of unlabeled FGLP2, the tumor uptake significantly decreased to 0.54 ± 0.05% ID/g at 30 min p.i.. Moreover, the uptake in U87 MG xenografts was 0.44 ± 0.06% ID/g at the same time point. The tracer was excreted mainly through the renal system. 18 F-FDG PET imaging was also performed in mice bearing Huh7 and U87 MG xenografts, respectively. However, there was no significant difference in the uptake between the tumors with different FGL1 expressions. Preclinical data indicated that 68 Ga-NOTA-FGLP2 might be a suitable radiotracer for in vivo noninvasive visualization of tumors with abundant expression of FGL1. Further investigation of 68 Ga-NOTA-FGLP2 for tumor diagnosis and therapy is undergoing.

show abstract

Section: Methodsmentioning

confidence: 99%

Synthesis and Characterization of a Novel PET Tracer for Noninvasive Evaluation of FGL1 Status in Tumors

Tan,

Ding,

Pan

et al. 2024

Mol. Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…It seems that FGL1-LAG-3 binding affected HCC CD8 + T RM cell activity, which highlights them as an immunotherapeutic target. 45 The pathogenesis of HCC recurrence following PH seems to involve (1) metabolic reprograming of proliferative cells and (2) alternation of growth factor production and hepatokine release. In the current review, we tried to explain some of these pathways, focusing on the role of FGL1.…”

Section: Hepatectomy In Patients With Hcc and The Possible Role Of Fgl1mentioning

confidence: 99%

Role of Fibrinogen-like Protein 1 in Tumor Recurrence Following Hepatectomy

Shafieizadeh,

Davoudi

et al. 2024

J Clin Transl Hepatol

View full text Add to dashboard Cite

Partial hepatectomy is a first-line treatment for hepatocellular carcinoma. Within 2 weeks following partial hepatectomy, specific molecular pathways are activated to promote liver regeneration. Nevertheless, residual microtumors may also exploit these pathways to reappear and metastasize. Therapeutically targeting molecules that are differentially regulated between normal cells and malignancies, such as fibrinogen-like protein 1 (FGL1), appears to be an effective approach. The potential functions of FGL1 in both regenerative and malignant cells are discussed within the ambit of this review. While FGL1 is normally elevated in regenerative hepatocytes, it is normally downregulated in malignant cells. Hepatectomy does indeed upregulate FGL1 by increasing the release of transcription factors that promote FGL1, including HNF-1α and STAT3, and inflammatory effectors, such as TGF-β and IL6. This, in turn, stimulates certain proliferative pathways, including EGFR/Src/ERK. Hepatectomy alters the phase transition of highly differentiated hepatocytes from G0 to G1, thereby transforming susceptible cells into cancerous ones. Activation of the PI3K/Akt/mTOR pathway by FGL1 allele loss on chromosome 8, a tumor suppressor area, may also cause hepatocellular carcinoma. Interestingly, FGL1 is specifically expressed in the liver via HNF-1α histone acetylase activity, which triggers lipid metabolic reprogramming in malignancies. FGL1 might also be involved in other carcinogenesis processes such as hypoxia, epithelial-mesenchymal transition, immunosuppression, and sorafenib-mediated drug resistance. This study highlights a research gap in these disciplines and the necessity for additional research on FGL1 function in the described processes.

show abstract

“…Loss of tumor suppressor PTEN or activity of the Wnt/βcatenin pathway, which are also linked to primary resistance (see above), can lead to immunosuppressive cytokine production and defective DC priming. 86,236 Upregulation of alternative immune checkpoints such as TIM-3 or LAG-3 contributes to T cell exhaustion 237,238 and their expression on (potential) APC can negatively influence the antigen presentation mechanisms. [239][240][241] Since data on acquired resistance are still sparse in liver cancer, the question remains whether (and how) to treat patients after acquired therapy failure.…”

Section: Mechanisms Of Acquired (Secondary) Resistancementioning

confidence: 99%

Overcoming Resistance to Immune Checkpoint Blockade in Liver Cancer with Combination Therapy: Stronger Together?

Werner,

Kuzminskaya,

Lurje

et al. 2024

Semin Liver Dis

View full text Add to dashboard Cite

Primary liver cancer, represented mainly by hepatocellular carcinoma (HCC) and intrahepatic cholangiocellular carcinoma (CCA), is one of the most common and deadliest tumors worldwide. While surgical resection or liver transplantation are the best option in early disease stages, these tumors often present in advanced stages and systemic treatment is required to improve survival time. The emergence of immune checkpoint inhibitor therapy has had a positive impact especially on the treatment of advanced cancers, thereby establishing immunotherapy as part of first-line treatment in HCC and CCA. Nevertheless, low response rates reflect on the usually cold or immunosuppressed tumor microenvironment of primary liver cancer. In this review, we aim to summarize mechanisms of resistance leading to tumor immune escape with a special focus on the composition of tumor microenvironment in both HCC and CCA, also reflecting on recent important developments in ICI combination therapy. Furthermore, we discuss how combination of immune checkpoint inhibitors with established primary liver cancer treatments (e.g. multikinase inhibitors and chemotherapy) as well as more complex combinations with state-of-the-art therapeutic concepts may re-shape the tumor microenvironment, leading to higher response rates and long-lasting anti-tumor immunity for primary liver cancer patients.

show abstract

Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma

Cited by 9 publications

References 40 publications

Synthesis and Characterization of a Novel PET Tracer for Noninvasive Evaluation of FGL1 Status in Tumors

Synthesis and Characterization of a Novel PET Tracer for Noninvasive Evaluation of FGL1 Status in Tumors

Role of Fibrinogen-like Protein 1 in Tumor Recurrence Following Hepatectomy

Overcoming Resistance to Immune Checkpoint Blockade in Liver Cancer with Combination Therapy: Stronger Together?

Contact Info

Product

Resources

About