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Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

ABSTRACT: 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.

SUBMITTER: Eggert T

PROVIDER: S-EPMC4234460 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

Eggert Tobias T Medina-Echeverz José J Kapanadze Tamar T Kruhlak Michael J MJ Korangy Firouzeh F Greten Tim F TF

PloS one 20141117 11

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) ...[more]

PMID: 25401795

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Project description:The establishment of primary tumor cells in distant organs, termed metastasis, is the principal cause of cancer mortality and is a crucial therapeutic target in oncology. Thus, it is critical to establish a better understanding of metastatic progression for the future development of improved therapeutic approaches. Indeed, such development requires insight into the timing of tumor cell dissemination and seeding of distant organs resulting in occult lesions. Following dissemination of tumor cells from the primary tumor, they can reside in niches in distant organs for years or decades, following which they can emerge as an overt metastasis. This timeline of metastatic dormancy is regulated by interactions between the tumor, its microenvironment, angiogenesis, and tumor antigen-specific T-cell responses. An improved understanding of the mechanisms and interactions responsible for immune evasion and tumor cell release from dormancy would help identify and aid in the development of novel targeted therapeutics. One such mediator of dormancy is myeloid derived suppressor cells (MDSC), whose number in the peripheral blood (PB) or infiltrating tumors has been associated with cancer stage, grade, patient survival, and metastasis in a broad range of tumor pathologies. Thus, extensive studies have revealed a role for MDSCs in tumor escape from adoptive and innate immune responses, facilitating tumor progression and metastasis; however, few studies have considered their role in dormancy. We have posited that MDSCs may regulate disseminated tumor cells resulting in resurgence of senescent tumor cells. In this review, we discuss clinical studies that address mechanisms of tumor recurrence including from dormancy, the role of MDSCs in their escape from dormancy during recurrence, the development of occult metastases, and the potential for MDSC inhibition as an approach to prolong the survival of patients with advanced malignancies. We stress that assessing the impact of therapies on MDSCs versus other cellular targets is challenging within the multimodality interventions required clinically.

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Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

Publications

Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

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