Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.
Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC) not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL), while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU) treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage.
Gastrointestinal Malignancy Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Tobias
T
Eggert
Gastrointestinal Malignancy Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
José
J
Medina-Echeverz
Gastrointestinal Malignancy Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Tamar
T
Kapanadze
Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Michael J
MJ
Kruhlak
Gastrointestinal Malignancy Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Firouzeh
F
Korangy
Gastrointestinal Malignancy Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Tim F
TF
Greten
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D016130:Immunophenotyping; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008546:Melanoma, Experimental; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D009369:Neoplasms / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D010641:Phenotype; D000637:Transaminases / Q000097:blood
D000954:Antigens, Surface; D016207:Cytokines; D000637:Transaminases