Abstract
Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that are increased in patients with numerous malignancies including viral-derived hepatocellular carcinoma (HCC). Here, we report an elevation of MDSC in other hepatobiliary malignancies including non-viral HCC, neuroendocrine tumors (NET), colorectal carcinoma with liver metastases (CRLM), but not cholangiocarcinoma (CCA). Investigation of myeloid cell infiltration in HCC, NET and intrahepatic CCA tumors further established that the frequency of antigen-presenting cells was limited compared to benign lesions suggesting that primary and metastatic hepatobiliary cancers have distinct peripheral and tumoral myeloid signatures. Bioinformatics analysis of the Cancer Genome Atlas demonstrated that a high MDSC score in HCC patients predicted poor disease outcome. Mechanistic studies indicated that the oncometabolite D-2-hydroxyglutarate resulting from isocitrate dehydrogenase 1 mutation could be a limiting factor of MDSC accumulation in CCA patients. Given our observation that MDSCs are increased in non-CCA malignant liver cancers, they may comprise suitable targets for effective immunotherapy approaches.
Footnotes
Conflict of Interest Statement: The authors declare no conflict of interest.
Financial Support Statement: This work was partially funded by the Cleveland Clinic Foundation Liver Cancer Center of Excellence (D.A., J.M.B. F.N.J. and J.D.L), the Case Comprehensive Cancer Center T32CA059366 (D.B.) and Ruth L. Kirschstein National Research Service Award (NRSA) Individual Postdoctoral Fellowship 1 F32 CA243314-01 (D.B.).
Abbreviations
- AFP
- Alpha-fetoprotein
- αKGα
- Alpha-ketoglutarate
- AST
- Aspartate aminotransferase
- ALT
- Alanine transaminase
- APC
- Antigen-presenting cells
- CCA
- Cholangiocarcinoma
- CEA
- Carcinoembryonic antigen
- CRLM
- Colorectal liver metastases
- D2HG
- D-2-Hydroxyglutarate
- DC
- Dendritic cell
- gMDSC
- Granulocytic myeloid-derived suppressor cells
- HCC
- Hepatocellular carcinoma
- MDSC
- Myeloid-derived suppressor cells
- mMDSC
- Monocytic myeloid-derived suppressor cells
- NET
- Neuroendocrine tumor
- PBMC
- Peripheral blood mononuclear cells
- TCGA
- The Cancer Genome Atlas
- Treg
- T regulatory cells
- WBC
- White blood cells