Top

Published in:

01-08-2015 | Review

Hepatic myeloid-derived suppressor cells in cancer

Authors: José Medina-Echeverz, Tobias Eggert, Miaojun Han, Tim F. Greten

Published in: Cancer Immunology, Immunotherapy | Issue 8/2015

Abstract

Myeloid-derived suppressor cells are key components of tumor-induced immune suppression. They are composed of a heterogeneous population of immature myeloid cells that abrogates innate and adaptive immune responses. Myeloid-derived suppressor cells accumulate not only in peripheral blood, secondary lymphoid organs and tumors, but also in the liver in preclinical tumor models and in hepatocellular carcinoma patients. The liver, continuously exposed to food and microbial antigens from the intestine, avoids autoimmune damage through the use of specialized mechanisms of immune tolerance. In the context of cancer, myeloid-derived suppressor cells profit the intrinsic tolerogenic properties of the liver to accumulate and exert various immune-suppressive and tumor-promoting mechanisms which go from inducing immune cell dysfunction to supporting the generation of liver metastases. In this review, we seek to describe the phenotype, function, accumulation and therapeutic targeting of hepatic myeloid-derived suppressor cells both in preclinical settings and in the context of human hepatocellular carcinoma.

Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12:253–268. doi:10.1038/nri3175 PubMedCentralPubMedCrossRef

Crispe IN (2009) The liver as a lymphoid organ. Annu Rev Immunol 27:147–163. doi:10.1146/annurev.immunol.021908.132629 PubMedCrossRef

Ilkovitch D, Lopez DM (2009) The liver is a site for tumor-induced myeloid-derived suppressor cell accumulation and immunosuppression. Cancer Res 69:5514–5521. doi:10.1158/0008-5472.CAN-08-4625 PubMedCentralPubMedCrossRef

Eggert T, Medina-Echeverz J, Kapanadze T, Kruhlak MJ, Korangy F, Greten TF (2014) Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage. PLoS One 9:e112717. doi:10.1371/journal.pone.0112717 PubMedCentralPubMedCrossRef

Kapanadze T, Gamrekelashvili J, Ma C et al (2013) Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma. J Hepatol 59:1007–1013. doi:10.1016/j.jhep.2013.06.010 PubMedCentralPubMedCrossRef

Connolly MK, Mallen-St Clair J, Bedrosian AS et al (2010) Distinct populations of metastases-enabling myeloid cells expand in the liver of mice harboring invasive and preinvasive intra-abdominal tumor. J Leukoc Biol 87:713–725. doi:10.1189/jlb.0909607 PubMedCentralPubMedCrossRef

Kapanadze T, Medina-Echeverz J, Gamrekelashvili J et al (2015) Tumor-induced CD11b Gr-1 myeloid-derived suppressor cells exacerbate immune mediated hepatitis in mice in a CD40-dependent manner. Eur J Immunol 45(4):1148–1158. doi:10.1002/eji.201445093 PubMedCrossRef

Zhao L, Lim SY, Gordon-Weeks AN et al (2013) Recruitment of a myeloid cell subset (CD11b/Gr1 mid) via CCL2/CCR2 promotes the development of colorectal cancer liver metastasis. Hepatology 57:829–839. doi:10.1002/hep.26094 PubMedCrossRef

Kitamura T, Fujishita T, Loetscher P, Revesz L, Hashida H, Kizaka-Kondoh S, Aoki M, Taketo MM (2010) Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model. Proc Natl Acad Sci USA 107:13063–13068. doi:10.1073/pnas.1002372107 PubMedCentralPubMedCrossRef

10.

Burga RA, Thorn M, Point GR et al (2015) Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T. Cancer Immunol Immunother. doi:10.1007/s00262-015-1692-6 PubMed

11.

Gonzalez-Aparicio M, Alzuguren P, Mauleon I et al (2011) Oxaliplatin in combination with liver-specific expression of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice. Gut 60:341–349. doi:10.1136/gut.2010.211722 PubMedCrossRef

12.

Gauttier V, Judor JP, Le Guen V, Cany J, Ferry N, Conchon S (2014) Agonistic anti-CD137 antibody treatment leads to antitumor response in mice with liver cancer. Int J Cancer 135:2857–2867. doi:10.1002/ijc.28943 PubMedCrossRef

13.

Ma S, Cheng Q, Cai Y et al (2014) IL-17A produced by gammadelta T cells promotes tumor growth in hepatocellular carcinoma. Cancer Res 74:1969–1982. doi:10.1158/0008-5472.CAN-13-2534 PubMedCrossRef

14.

Schmidt K, Zilio S, Schmollinger JC, Bronte V, Blankenstein T, Willimsky G (2013) Differently immunogenic cancers in mice induce immature myeloid cells that suppress CTL in vitro but not in vivo following transfer. Blood 121:1740–1748. doi:10.1182/blood-2012-06-436568 PubMedCrossRef

15.

Talmadge JE, Gabrilovich DI (2013) History of myeloid-derived suppressor cells. Nat Rev Cancer 13:739–752. doi:10.1038/nrc3581 PubMedCentralPubMedCrossRef

16.

Li H, Han Y, Guo Q, Zhang M, Cao X (2009) Cancer-Expanded Myeloid-Derived Suppressor Cells Induce Anergy of NK Cells through Membrane-Bound TGF-1. J Immunol 182:240–249. doi:10.4049/jimmunol.182.1.240 PubMedCrossRef

17.

Youn JI, Collazo M, Shalova IN, Biswas SK, Gabrilovich DI (2012) Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J Leukoc Biol 91:167–181. doi:10.1189/jlb.0311177 PubMedCentralPubMedCrossRef

18.

Fridlender ZG, Sun J, Mishalian I et al (2012) Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils. PLoS One 7:e31524. doi:10.1371/journal.pone.0031524 PubMedCentralPubMedCrossRef

19.

Haverkamp JM, Crist SA, Elzey BD, Cimen C, Ratliff TL (2011) In vivo suppressive function of myeloid-derived suppressor cells is limited to the inflammatory site. Eur J Immunol 41:749–759. doi:10.1002/eji.201041069 PubMedCentralPubMedCrossRef

20.

Bronte V, Zanovello P (2005) Regulation of immune responses by l-arginine metabolism. Nat Rev Immunol 5:641–654. doi:10.1038/nri1668 PubMedCrossRef

21.

Medina-Echeverz J, Ma C, Duffy A, Eggert T, Hawk N, Kleiner DE, Korangy F, Greten TF (2015) Systemic agonistic anti-CD40 treatment of tumor bearing mice modulates hepatic myeloid suppressive cells and causes immune-mediated liver damage. Cancer Immunol Res 3(5):557–566. doi:10.1158/2326-6066.CIR-14-0182 PubMedCrossRef

22.

Lu T, Gabrilovich DI (2012) Molecular pathways: tumor-infiltrating myeloid cells and reactive oxygen species in regulation of tumor microenvironment. Clin Cancer Res 18:4877–4882. doi:10.1158/1078-0432.CCR-11-2939 PubMedCentralPubMedCrossRef

23.

Lalor PF, Adams DH (2002) The liver: a model of organ-specific lymphocyte recruitment. Expert Rev Mol Med 4:1–16. doi:10.1017/S1462399402004155 PubMedCrossRef

24.

Majumdar A, Curley SA, Wu X et al (2012) Hepatic stem cells and transforming growth factor beta in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 9:530–538. doi:10.1038/nrgastro.2012.114 PubMedCentralPubMedCrossRef

25.

Thorn M, Point GR, Burga RA, Nguyen CT, Joseph Espat N, Katz SC (2014) Liver metastases induce reversible hepatic B cell dysfunction mediated by Gr-1+ CD11b+ myeloid cells. J Leukoc Biol 96:883–894. doi:10.1189/jlb.3A0114-012RR PubMedCrossRef

26.

Schneider C, Teufel A, Yevsa T et al (2012) Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer. Gut 61:1733–1743. doi:10.1136/gutjnl-2011-301116 PubMedCrossRef

27.

Nefedova Y, Huang M, Kusmartsev S, Bhattacharya R, Cheng P, Salup R, Jove R, Gabrilovich D (2004) Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J Immunol 172:464–474PubMedCrossRef

28.

Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182:4499–4506. doi:10.4049/jimmunol.0802740 PubMedCentralPubMedCrossRef

29.

Sawanobori Y, Ueha S, Kurachi M et al (2008) Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood 111:5457–5466. doi:10.1182/blood-2008-01-136895 PubMedCrossRef

30.

Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8:618–631. doi:10.1038/nrc2444 PubMedCrossRef

31.

Lim SY, Gordon-Weeks AN, Zhao L et al (2013) Recruitment of myeloid cells to the tumor microenvironment supports liver metastasis. Oncoimmunology 2:e23187. doi:10.4161/onci.23187 PubMedCentralPubMedCrossRef

32.

Wu D, Wu P, Huang Q, Liu Y, Ye J, Huang J (2013) Interleukin-17: a promoter in colorectal cancer progression. Clin Dev Immunol 2013:436307. doi:10.1155/2013/436307 PubMedCentralPubMed

33.

Seki E, de Minicis S, Inokuchi S, Taura K, Miyai K, van Rooijen N, Schwabe RF, Brenner DA (2009) CCR2 promotes hepatic fibrosis in mice. Hepatology 50:185–197. doi:10.1002/hep.22952 PubMedCentralPubMedCrossRef

34.

Si Y, Tsou CL, Croft K, Charo IF (2010) CCR2 mediates hematopoietic stem and progenitor cell trafficking to sites of inflammation in mice. J Clin Invest 120:1192–1203. doi:10.1172/JCI40310 PubMedCentralPubMedCrossRef

35.

Zimmermann HW, Trautwein C, Tacke F (2012) Functional role of monocytes and macrophages for the inflammatory response in acute liver injury. Front Physiol 3:56. doi:10.3389/fphys.2012.00056 PubMedCentralPubMedCrossRef

36.

Lim SY, Gordon-Weeks A, Allen D, Kersemans V, Beech J, Smart S, Muschel RJ (2015) CD11b myeloid cells support hepatic metastasis through downregulation of Angiopoietin-like 7 in cancer cells. Hepatology. doi:10.1002/hep.27838 PubMedCentral

37.

Greten TF, Manns MP, Korangy F (2011) Myeloid derived suppressor cells in human diseases. Int Immunopharmacol 11:802–807. doi:10.1016/j.intimp.2011.01.003 PubMedCentralPubMedCrossRef

38.

Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Kruger C, Manns MP, Greten TF, Korangy F (2008) A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 135:234–243. doi:10.1053/j.gastro.2008.03.020 PubMedCrossRef

39.

Kalathil S, Lugade AA, Miller A, Iyer R, Thanavala Y (2013) Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality. Cancer Res 73:2435–2444. doi:10.1158/0008-5472.CAN-12-3381 PubMedCentralPubMedCrossRef

40.

Hoechst B, Voigtlaender T, Ormandy L et al (2009) Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50:799–807. doi:10.1002/hep.23054 PubMedCrossRef

41.

Hochst B, Schildberg FA, Sauerborn P et al (2013) Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion. J Hepatol 59:528–535. doi:10.1016/j.jhep.2013.04.033 PubMedCrossRef

42.

Resheq YJ, Li KK, Ward ST et al (2015) Contact-dependent depletion of hydrogen peroxide by catalase is a novel mechanism of myeloid-derived suppressor cell induction operating in human hepatic stellate cells. J Immunol 194:2578–2586. doi:10.4049/jimmunol.1401046 PubMedCrossRef

43.

Duffy A, Zhao F, Haile L et al (2013) Comparative analysis of monocytic and granulocytic myeloid-derived suppressor cell subsets in patients with gastrointestinal malignancies. Cancer Immunol Immunother 62:299–307. doi:10.1007/s00262-012-1332-3 PubMedCrossRef

44.

Yen BL, Yen ML, Hsu PJ, Liu KJ, Wang CJ, Bai CH, Sytwu HK (2013) Multipotent human mesenchymal stromal cells mediate expansion of myeloid-derived suppressor cells via hepatocyte growth factor/c-met and STAT3. Stem Cell Rep 1:139–151. doi:10.1016/j.stemcr.2013.06.006 CrossRef

45.

Oleinika K, Nibbs RJ, Graham GJ, Fraser AR (2013) Suppression, subversion and escape: the role of regulatory T cells in cancer progression. Clin Exp Immunol 171:36–45. doi:10.1111/j.1365-2249.2012.04657.x PubMedCentralPubMedCrossRef

46.

Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586–2593. doi:10.1200/JCO.2006.09.4565 PubMedCrossRef

47.

Fu J, Xu D, Liu Z et al (2007) Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132:2328–2339. doi:10.1053/j.gastro.2007.03.102 PubMedCrossRef

48.

Yang XH, Yamagiwa S, Ichida T et al (2006) Increase of CD4+ CD25+ regulatory T-cells in the liver of patients with hepatocellular carcinoma. J Hepatol 45:254–262. doi:10.1016/j.jhep.2006.01.036 PubMedCrossRef

49.

Ma C, Kapanadze T, Gamrekelashvili J, Manns MP, Korangy F, Greten TF (2012) Anti-Gr-1 antibody depletion fails to eliminate hepatic myeloid-derived suppressor cells in tumor-bearing mice. J Leukoc Biol 92:1199–1206. doi:10.1189/jlb.0212059 PubMedCentralPubMedCrossRef

50.

Qin H, Lerman B, Sakamaki I et al (2014) Generation of a new therapeutic peptide that depletes myeloid-derived suppressor cells in tumor-bearing mice. Nat Med 20:676–681. doi:10.1038/nm.3560 PubMedCentralPubMedCrossRef

51.

Cao M, Xu Y, Youn JI, Cabrera R, Zhang X, Gabrilovich D, Nelson DR, Liu C (2011) Kinase inhibitor Sorafenib modulates immunosuppressive cell populations in a murine liver cancer model. Lab Invest 91:598–608. doi:10.1038/labinvest.2010.205 PubMedCentralPubMedCrossRef

52.

Chen Y, Ramjiawan RR, Reiberger T et al (2015) CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology 61(5):1591–1602. doi:10.1002/hep.27665 PubMedCrossRef

53.

Cheng AL, Kang YK, Lin DY et al (2013) Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 31:4067–4075. doi:10.1200/JCO.2012.45.8372 PubMedCrossRef

54.

Ozao-Choy J, Ma G, Kao J et al (2009) The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res 69:2514–2522. doi:10.1158/0008-5472.CAN-08-4709 PubMedCentralPubMedCrossRef

55.

Eisenstein S, Coakley BA, Briley-Saebo K et al (2013) Myeloid-derived suppressor cells as a vehicle for tumor-specific oncolytic viral therapy. Cancer Res 73:5003–5015. doi:10.1158/0008-5472.CAN-12-1597 PubMedCentralPubMedCrossRef

56.

Cheng L, Wang J, Li X, Xing Q, Du P, Su L, Wang S (2011) Interleukin-6 induces Gr-1+ CD11b+ myeloid cells to suppress CD8+ T cell-mediated liver injury in mice. PLoS One 6:e17631. doi:10.1371/journal.pone.0017631 PubMedCentralPubMedCrossRef

57.

Califano JA, Khan Z, Noonan KA et al (2015) Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res 21:30–38. doi:10.1158/1078-0432.CCR-14-1716 PubMedCrossRef

58.

Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD, Stanger BZ, Vonderheide RH (2012) Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21:822–835. doi:10.1016/j.ccr.2012.04.025 PubMedCentralPubMedCrossRef

59.

Yamada D, Rizvi S, Razumilava N et al (2015) IL-33 facilitates oncogene-induced cholangiocarcinoma in mice by an interleukin-6-sensitive mechanism. Hepatology 61(5):1627–1642. doi:10.1002/hep.27687 PubMedCentralPubMedCrossRef

60.

MacKinnon AC, Farnworth SL, Hodkinson PS et al (2008) Regulation of alternative macrophage activation by galectin-3. J Immunol 180:2650–2658PubMedCrossRef

61.

Hassan MM, Abdel-Wahab R, Kaseb A et al (2015) Obesity Early in Adulthood Increases Risk but Does Not Affect Outcomes of Hepatocellular Carcinoma. Gastroenterology. doi:10.1053/j.gastro.2015.03.044 PubMedCentral

62.

Deng ZB, Liu Y, Liu C et al (2009) Immature myeloid cells induced by a high-fat diet contribute to liver inflammation. Hepatology 50:1412–1420. doi:10.1002/hep.23148 PubMedCentralPubMedCrossRef

Title: Hepatic myeloid-derived suppressor cells in cancer
Authors: José Medina-Echeverz
Tobias Eggert
Miaojun Han
Tim F. Greten
Publication date: 01-08-2015
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 8/2015
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-015-1736-y

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 8/2015

STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice

Optimal selection of natural killer cells to kill myeloma: the role of HLA-E and NKG2A

Idiotypic DNA vaccination for the treatment of multiple myeloma: safety and immunogenicity in a phase I clinical study

6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice

Cytokine production in patients with papillary thyroid cancer and associated autoimmune Hashimoto thyroiditis

CD163+CD14+ macrophages, a potential immune biomarker for malignant pleural effusion

Keynote webinar | Spotlight on antibody–drug conjugates in cancer