A New Population of Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma Patients Induces CD4+CD25+Foxp3+ T Cells

Hoechst, Bastian; Ormandy, Lars A.; Ballmaier, Matthias; Lehner, Frank; Krüger, Caroline; Manns, Michael P.; Greten, Tim F.; Korangy, Firouzeh

doi:10.1053/j.gastro.2008.03.020

Cited by 715 publications

(702 citation statements)

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“…MDSCs are found in both tumor tissues and peripheral blood from patients with HCC, and elevated MDSC numbers correlated with clinical tumor progression. 39,40 Reducing the numbers of MDSCs in murine tumors markedly improved the antitumor responses of chemotherapy. 8 In human, myeloid-derived suppressor cells as an immune parameter in patients with concurrent sunitinib and stereotactic body radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Tsai

Lee

et al. 2018

OncoImmunology

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Immunotherapies have shown promising results in certain cancer patients. For hepatocellular carcinoma (HCC), the multiplicity of an immunotolerant microenvironment within both the tumor, and the liver per se may limit the efficacy of cancer immunotherapies. Since radiation induces immunogenic cell death and inflammatory reactions within the tumor microenvironment, we hypothesized that a combination therapy of radiation and lasting local immunostimulating agents, achieved by intratumoral injection of an adenoviral vector encoding interleukin 12, may reverse the immunotolerant microenvironment within a well-established orthotopic HCC toward a state favorable for inducing antitumor immunities. Our data showed that radiation and IL-12 combination therapy (RT/IL-12) led to dramatic tumor regression in animals bearing large subcutaneous or orthotopic HCC, induced systemic effect against distant tumor, and significantly prolonged survival. Radiation monotherapy induced tumor regression at early times but afterwards most tumors regained exponential growth, while IL-12 monotherapy only delayed tumor growth. Mechanistic studies revealed that RT/IL-12 increased expression of MHC class II and co-stimulatory molecules CD40 and CD86 on tumor-infiltrating dendritic cells, suggesting an improvement of their antigen presentation activity. RT/IL-12 also significantly reduced accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) and impaired their suppressive functions by reducing production of reactive oxygen species. Accordingly, tumor-infiltrating CD8+ T cells and NK cells were significantly activated toward the antitumor phenotype, as revealed by increased expression of CD107a and TNF-α. Together, our data showed that RT/IL-12 treatment could reset the intratumoral immunotolerant state and stimulate activation of antitumor cellular immunity that is capable of eliminating large established HCC tumors.

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Section: Discussionmentioning

confidence: 99%

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Tsai

Lee

et al. 2018

OncoImmunology

View full text Add to dashboard Cite

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“…They have been shown to accumulate in human HCC and suppress the anti-tumor immune response [55,56]. MDSCs expand in the bone marrow in response to proinflammatory cytokines in cancer or chronic inflammation and subsequently exit the bone marrow and seed at sites of tumor/inflammation.…”

Section: Discussionmentioning

confidence: 99%

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b⁺Gr1⁺ cells in carbon tetrachloride‐induced liver injury in mice

et al. 2015

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Interleukin-1α is mainly expressed on the cell membrane, but can also be secreted during inflammation. The roles of secreted and membrane IL-1α in acute liver inflammation are still not known. Here, we examined the functions of secreted and membrane IL-1α in a mouse model of carbon tetrachloride-induced acute liver injury. We show that secreted IL-1α aggravates liver damage and membrane IL-1α slightly protects mice from liver injury. Further studies showed that secreted IL-1α promotes T-cell activation. It also increased the expansion of CD11b + Gr1 + myeloid cells, which may serve as a negative regulator of acute liver inflammation. Moreover, secreted IL-1α induced IL-6 production from hepatocytes. IL-6 neutralization reduced the proliferation of CD11b + Gr1 + myeloid cells in vivo. CCL2 and CXCL5 expression was increased by secreted IL-1α in vitro and in vivo. Antagonists of the chemokine receptors for CCL2 and CXCL5 significantly reduced the migration of CD11b + Gr1 + myeloid cells. These results demonstrate that secreted and membrane IL-1α play different roles in acute liver injury. Secreted IL-1α could promote Tcell activation and the recruitment and expansion of CD11b + Gr1 + myeloid cells through induction of CCL2, CXCL5, and IL-6. The controlled release of IL-1α could be a critical regulator during acute liver inflammation.Keywords: Acute liver injury r CD11b + Gr1 + myeloid cells r Membrane IL-1α r Secreted IL-1α r T-cell activation Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Haiyan Liu e-mail: hliu@suda.edu.cn IntroductionThe liver plays a central role in metabolic homeostasis [1]. Liver injury is mainly caused by various insults such as drug, chemical agents, viral hepatitis (hepatitis B or C viruses), alcohol, and C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 2084-2098 Molecular immunology 2085 autoimmune attack of hepatocytes [2]. Liver damage by proinflammatory cytokines induced by these causes is a relevant mechanism for liver cell death [3]. Acute liver injury remains one of the most challenging problems in liver diseases, and new therapeutic options for treatment of acute liver injury are urgently needed [4]. Carbon tetrachloride (CCl 4 ) is widely used as a chemical inducer of acute or chronic liver injury in rodents depending on the dosage and administration frequency [5]. ROS and oxidative stress are then generated and inflammatory cells are recruited, which leads to hepatocyte degeneration and necrosis [6,7]. Parenchymal cells could regenerate that involves a complex regulated response after CCl 4 -induced acute liver injury [8]. Therefore, anti-oxidative and anti-inflammatory therapies are thought to be the effective ways to prevent and attenuate CCl 4 -induced liver damage. IL-1 is a pleiotropic cytokine and affects inflammatory immune responses. The IL-1 family includes two important agonistic proteins, IL-1α and IL-1β, which play an important role in ...

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“…HLA-DR loss on CD14 C monocytes has been shown to be a major event in tumor-induced immunosuppression. [11][12][13][14][15][16][17][18] We have shown in our results that this population of immunosuppressive monocytes is elevated in PC in terms of the percentage of total monocytes and in cell count (data not shown) ( Fig. 2A, left panel).…”

Section: Immunophenotypic Changes In Pc Patientsmentioning

confidence: 54%

Immunosuppressive CD14⁺HLA-DR^lo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

et al. 2016

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Immunological strategies to treat pancreatic cancer offer new therapeutic approaches to improve patient outcomes. Understanding alterations in the immune systems of pancreatic cancer patients will likely lead to advances in immunotherapy for the disease. We profiled peripheral blood leukocytes from pancreatic cancer patients (n D 22) and age-matched controls (n D 20) using flow cytometry. Immune profiling of pancreatic cancer patients identified phenotypic changes in various immune cell populations, including a population of immunosuppressive monocytes (CD14 C HLA-DR lo/neg ), which were shown to be increased in these patients. There was a correlation between the levels of CD14 C monocytes and the levels of CD14 C HLA-DR lo/neg monocytes in peripheral blood from pancreatic cancer patients. HLA-DR downregulation of monocytes was shown to occur through pancreatic cancer-derived exosome interactions with monocytes. In an in vitro model, exosomes from patient-derived xenograft cell lines and patient plasma decreased HLA-DR expression on CD14 C monocytes. Additionally, tumor-derived exosomes caused immune suppression in monocytes through altered STAT3 signaling, induction of arginase expression, and reactive oxygen species. These findings provide novel insights into the mechanisms that govern immunosuppression in pancreatic cancer. Understanding monocyte-exosome interactions could lead to novel immunotherapies for this disease.

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A New Population of Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma Patients Induces CD4+CD25+Foxp3+ T Cells

Cited by 715 publications

References 28 publications

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b⁺Gr1⁺ cells in carbon tetrachloride‐induced liver injury in mice

Immunosuppressive CD14⁺HLA-DR^lo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

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A New Population of Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma Patients Induces CD4+CD25+Foxp3+ T Cells

Cited by 715 publications

References 28 publications

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b+Gr1+ cells in carbon tetrachloride‐induced liver injury in mice

Immunosuppressive CD14+HLA-DRlo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

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Secreted IL‐1α promotes T‐cell activation and expansion of CD11b⁺Gr1⁺ cells in carbon tetrachloride‐induced liver injury in mice

Immunosuppressive CD14⁺HLA-DR^lo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes