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1.
Cancer Lett ; 513: 14-25, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-33992711

RESUMO

Immune checkpoint blockade is considered a breakthrough in cancer treatment. However, with the low response rates and therapeutic resistance of patients with hepatocellular carcinoma (HCC), the challenges facing the application of this treatment are tremendous. Liver fibrosis is a key driver of tumor immune escape, the underlying mechanism has never been clarified. This study sought to explore the role of liver fibrosis in regulating tumor-infiltrating lymphocytes (TILs) and inducing tumor immunosuppression. Ninety-nine fixed HCC tissue samples were used to analyze the association between liver fibrosis and immune escape using immunohistochemistry. In HCC patients, low FIB-4 values and high CD8+ T cell infiltration were correlated with prolonged survival. Elevated expression of immune checkpoints and attenuated antitumor immunity were observed in CCl4-induced mice liver fibrosis models and human fibrotic livers compared to control group. GOLM1 levels were increased in livers of patients with fibrosis and mice in response to CCl4-induced liver fibrosis. CD8+ T cell infiltrations were significantly decreased and PD-L1 expression was significantly increased in tumor tissues from hepatocyte-specific GOLM1 transgenic mice (Alb/GOLM1 mice) inducing chemical carcinogenesis compared to their corresponding control WT mice. GOLM1 induced PD-L1 expression via EGFR pathway activation. EGFR inhibitors, especially together with anti-PD-L1 therapy, improved the efficacy of immunotherapy in HCC. These findings illustrate the importance of liver fibrosis-induced immunosuppression as a tumor-promoting mechanism. GOLM1, which is highly upregulated in the fibrotic liver, regulates tumor microenvironmental immune escape via the EGFR/PD-L1 signaling pathway. EGFR blockade may bolster the efficacy of immune checkpoint inhibitors for HCC treatment.


Assuntos
Antígeno B7-H1/imunologia , Carcinoma Hepatocelular/imunologia , Cirrose Hepática/imunologia , Neoplasias Hepáticas/imunologia , Proteínas de Membrana/imunologia , Animais , Antígeno B7-H1/biossíntese , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Humanos , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Evasão Tumoral , Microambiente Tumoral , Regulação para Cima
2.
World J Gastroenterol ; 23(46): 8217-8226, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29290658

RESUMO

AIM: To explore the possible relationship between fecal microbial communities and non-anastomotic stricture (NAS) after liver transplantation (LT). METHODS: A total of 30 subjects including 10 patients with NAS, 10 patients with no complications after LT, and 10 non-LT healthy individuals were enrolled. Fecal microbial communities were assessed by the 16S rRNA gene sequencing technology. RESULTS: Different from the uncomplicated and healthy groups, unbalanced fecal bacterium ratio existed in patients with NAS after LT. The results showed that NAS patients were associated with a decrease of Firmicutes and Bacteroidetes and an increase of Proteobacteria at the phylum level, with the proportion-ratio imbalance between potential pathogenic families including Enterococcaceae, Streptococcaceae, Enterobacteriaceae, Pseudomonadaceae and dominant families including Bacteroidaceae. CONCLUSION: The compositional shifts of the increase of potential pathogenic bacteria as well as the decrease of dominant bacteria might contribute to the incidence of NAS.


Assuntos
Bactérias/isolamento & purificação , Doenças Biliares/microbiologia , Fezes/microbiologia , Microbioma Gastrointestinal , Transplante de Fígado/efeitos adversos , Adulto , Bactérias/genética , Bactérias/patogenicidade , Doenças Biliares/etiologia , Constrição Patológica/etiologia , Constrição Patológica/microbiologia , DNA Bacteriano/isolamento & purificação , Disbiose/etiologia , Disbiose/microbiologia , Doença Hepática Terminal/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
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