Gut Microbiome Directs Hepatocytes to Recruit MDSCs and Promote Cholangiocarcinoma

Zhang, Qianfei; Ma, Chi; Duan, Yi; Heinrich, Bernd; Rosato, Umberto; Diggs, Laurence P.; Roy, Soumen; Fu, Qiong; Brown, Zachary J.; Wabitsch, Simon; Thovarai, Vishal; Fu, Jianyang; Feng, Dechun; Ruf, Benjamin; Cui, Linda L.; Subramanyam, Varun; Frank, Karen M.; Wang, Xin Wei; Kleiner, David E.; Ritz, Thomas; Rupp, Christian; Gao, Bin; Longerich, Thomas; Kroemer, Alexander; Ruchirawat, Mathuros; Korangy, Firouzeh; Schnabl, Bernd; Trinchieri, Giorgio; Greten, Tim F.

doi:10.1158/2159-8290.cd-20-0304

Cited by 144 publications

(126 citation statements)

References 86 publications

Supporting

Mentioning

109

Contrasting

Order By: Relevance

“…Hepatocytes secreted CXCL1, a chemokine responsible for PMN-MDSC recruitment, upon interaction with Gram-negative bacteria via their TLR4. Intrahepatic cholangiocarcinoma patient data also support the role of bacteria in tumor progression, which shows that those with lower expression of TLR4 have longer overall survival [127]. Gut dysbiosis that occurs after exposure to the carcinogenic compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) also leads to an accumulation of MDSCs in the peritoneal cavity of mice [128].…”

Section: Mdscs and Microbiomementioning

confidence: 88%

Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Cancer and Immunotherapy

Krishnamoorthy

Gerhardt

Vareki

2021

Cells

View full text Add to dashboard Cite

The primary function of myeloid cells is to protect the host from infections. However, during cancer progression or states of chronic inflammation, these cells develop into myeloid-derived suppressor cells (MDSCs) that play a prominent role in suppressing anti-tumor immunity. Overcoming the suppressive effects of MDSCs is a major hurdle in cancer immunotherapy. Therefore, understanding the mechanisms by which MDSCs promote tumor growth is essential for improving current immunotherapies and developing new ones. This review explores mechanisms by which MDSCs suppress T-cell immunity and how this impacts the efficacy of commonly used immunotherapies.

show abstract

Section: Mdscs and Microbiomementioning

confidence: 88%

Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Cancer and Immunotherapy

Krishnamoorthy

Gerhardt

Vareki

2021

Cells

View full text Add to dashboard Cite

show abstract

“…The murine CCA cell lines SB1 24 and LD-1, as well as the human CAA cell line EGI-1, 25 were used in this study. LD-1 26 was established in our laboratory and is derived from a mouse after hydrodynamic injection with AKT and YAP plasmids. WES data from LD-1 as well as SB1 will be provided upon request.…”

Section: Methodsmentioning

confidence: 99%

Anti–PD-1 in Combination With Trametinib Suppresses Tumor Growth and Improves Survival of Intrahepatic Cholangiocarcinoma in Mice

Wabitsch¹,

Tandon

Ruf³

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

Self Cite

View full text Add to dashboard Cite

Immune checkpoint inhibitors are not available for intrahepatic cholangiocarcinoma. Here, we show that trametinib improves the immunogenicity of tumor cells, leading to a robust response of the combination of trametinib and anti-PD-1 in different preclinical models.BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) accounts for a fraction of primary liver cancers but has a 5-year survival rate of only 10%. Immune checkpoint inhibitors are effective in treating many solid cancers, but immune checkpoint inhibitor monotherapy has no clear benefit in iCCA. MEK Q9 inhibitors, such as trametinib, have shown promising results in preclinical studies for iCCA by inhibiting cell proliferation and modifying the tumor microenvironment. This study aimed to show the potential benefit of combining trametinib with anti-PD Q10 -1 therapy in different iCCA mouse models.METHODS: Here, we assessed the in vitro cytotoxicity of trametinib in mouse (SB1 and LD-1) and human (EGI-1) cholangiocarcinoma cell lines. We examined the efficacy of singleagent trametinib, anti-PD-1, and a combination of both in subcutaneous, orthotopic, and plasmid-induced iCCA mouse models. Flow cytometry analysis was used to elucidate changes in the tumor immune microenvironment upon treatment. Whole-exome sequencing (WES) was performed on the SB1 tumor cell line to correlate this preclinical model with iCCAs in patients.RESULTS: Trametinib reduced tumor cell growth of SB1, LD-1, and EGI-1 tumor cells in vitro. Trametinib treatment led to upregulation of MHC-I and PD-L1 on tumor cells in vitro. The combination of trametinib and anti-PD-1 reduced tumor burden in several iCCA tumor models and improved survival in SB1 tumor-bearing mice compared with either agent alone. Immunoprofiling of tumor-bearing mice showed an increase of hepatic effector memory CD8 þ and CD4 þ T cells, as well as an increased degranulation of CD8 þ T cells, indicating enhanced cytotoxicity. WES and somatic mutational analysis showed no mutations of KRAS, BRAF, and ERK in SB1 tumor cells, and showed a similar genetic signature of SB1 found in a cohort of patients with iCCA.CONCLUSIONS: Altogether, our study shows that trametinib improves the immunogenicity of tumor cells by up-regulating MHC-I surface expression. The combination with anti-PD-1 results in optimal treatment efficacy for iCCA. WES of SB1 cells

show abstract

“…Although the exact mechanisms remain unclear, several studies could serve as valuable references for us to speculate how gut microbiome promoted the accumulation of MDSC. Recently, Zhang et al 133 demonstrated that in the mice models of Cholangiocarcinoma, an impairment of gut barrier could result in the migration of gut-derived bacteria to the liver, which induced CXCL1 secretion from hepatocytes through TLR4 pathway and subsequently caused PMN-MDSC accumulation. This means that the gut microbiota could serve as pathogen-associated molecular patterns to interact with the pattern-related receptors and create an immunosuppressive environment in the target organ through induction of MDSC-recruiting cytokines and chemokines.…”

Section: The Interactions Between Mdsc and Other Components In The Tmementioning

confidence: 99%

Targeting MDSC for Immune-Checkpoint Blockade in Cancer Immunotherapy: Current Progress and New Prospects

Liu

Zhu

et al. 2021

Clin Med Insights Oncol

View full text Add to dashboard Cite

Immune-checkpoint blockade (ICB) demonstrated inspiring effect and great promise in anti-cancer therapy. However, many obstacles, such as drug resistance and difficulty in patient selection, limited the efficacy of ICB therapy and awaited to be overcome. By timely identification and intervention of the key immune-suppressive promotors in the tumor microenvironment (TME), we may better understand the mechanisms of cancer immune-escape and use novel strategies to enhance the therapeutic effect of ICB. Myeloid-derived suppressor cell (MDSC) is recognized as a major immune suppressor in the TME. In this review, we summarized the roles MDSC played in the cancer context, focusing on its negative biologic functions in ICB therapy, discussed the strategies targeted on MDSC to optimize the diagnosis and therapy process of ICB and improve the efficacy of ICB therapy against malignancies.

show abstract

Gut Microbiome Directs Hepatocytes to Recruit MDSCs and Promote Cholangiocarcinoma

Cited by 144 publications

References 86 publications

Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Cancer and Immunotherapy

Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Cancer and Immunotherapy

Anti–PD-1 in Combination With Trametinib Suppresses Tumor Growth and Improves Survival of Intrahepatic Cholangiocarcinoma in Mice

Targeting MDSC for Immune-Checkpoint Blockade in Cancer Immunotherapy: Current Progress and New Prospects

Contact Info

Product

Resources

About