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Interactions among myeloid regulatory cells in cancer

  • Viktor Umansky
  • Gosse J. Adema
  • Jaroslaw Baran
  • Sven Brandau
  • Jo A. Van Ginderachter
  • Xiaoying Hu
  • Jadwiga Jablonska
  • Slavko Mojsilovic
  • Helen A. Papadaki
  • Yago Pico de Coaña
  • Kim C. M. Santegoets
  • Juan F. Santibanez
  • Karine Serre
  • Yu Si
  • Isabela Sieminska
  • Maria Velegraki
  • Zvi G. Fridlender
Symposium-in-Writing Paper

Abstract

Mounting evidence has accumulated on the critical role of the different myeloid cells in the regulation of the cancerous process, and in particular in the modulation of the immune reaction to cancer. Myeloid cells are a major component of host cells infiltrating tumors, interacting with each other, with tumor cells and other stromal cells, and demonstrating a prominent plasticity. We describe here various myeloid regulatory cells (MRCs) in mice and human as well as their relevant therapeutic targets. We first address the role of the monocytes and macrophages that can contribute to angiogenesis, immunosuppression and metastatic dissemination. Next, we discuss the differential role of neutrophil subsets in tumor development, enhancing the dual and sometimes contradicting role of these cells. A heterogeneous population of immature myeloid cells, MDSCs, was shown to be generated and accumulated during tumor progression as well as to be an important player in cancer-related immune suppression. Lastly, we discuss the role of myeloid DCs, which can either contribute to effective anti-tumor responses or play a more regulatory role. We believe that MRCs play a critical role in cancer-related immune regulation and suggest that future anti-cancer therapies will focus on these abundant cells.

Keywords

Myeloid regulatory cells Mye-EUNITER Macrophages Neutrophils Myeloid-derived suppressor cells Dendritic cells 

Abbreviations

Arg

Arginase

CCL

C–C motif ligand

cDC

Classical dendritic cell

CXCL

C–X–C motif ligand

DCs

Dendritic cells

EBV

Epstein–Barr virus

EGF

Epidermal growth factor

FGF

Fibroblast growth factor

HDNs

High-density neutrophils

HGF

Hepatocyte growth factor

iNOS

Inducible NO synthase

LDNs

Low-density neutrophils

LFA

Lymphocyte function-associated antigen

Mac

Macrophage antigen

M-CSF

Macrophage colony-stimulating factor

M-MDSCs

Monocytic MDSCs

MMPs

Matrix metalloproteinases

MRCs

Myeloid regulatory cells

NLR

Neutrophil to lymphocyte ratio

PDGF

Platelet-derived growth factor

PLGF

Placenta growth factor

PMN-MDSCs

Polymorphonuclear MDSCs

TAMs

Tumor-associated macrophages

TANs

Tumor-associated neutrophils

TGF

Transforming growth factor

Notes

Author contributions

VU, ZGF: writing and revision of the manuscript, revision of the tables and figures. GA, JB, SB, JAVG, JJ, HAP, KCMS, JFS, KS, MV: writing and revision of the manuscript and preparation of the tables. YPC, IS: preparation of the figures. XH, SM, YS: revision of the manuscript and figures.

Funding

This work was supported by COST (European Cooperation in Science and Technology) and the COST Action BM1404 Mye-EUNITER (http://www.mye-euniter.eu). COST is part of the EU Framework Programme Horizon 2020. This work was also supported by Grants from the Cooperation between German Cancer Research Center (DKFZ) and Ministry of Science, Technology and Space of Israel (MOST) in Cancer Research (CA181 to V. Umansky and Z.G. Fridlender).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Giraldo NA, Becht E, Remark R, Damotte D, Sautès-Fridman C, Fridman WH (2014) The immune contexture of primary and metastatic human tumours. Curr Opin Immunol 27:8–15PubMedCrossRefGoogle Scholar
  2. 2.
    Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T (2014) Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer 14:135–146PubMedCrossRefGoogle Scholar
  3. 3.
    Bonavita E, Galdiero MR, Jaillon S, Mantovani A (2015) Phagocytes as corrupted policemen in cancer-related inflammation. Adv Cancer Res 128:141–171PubMedCrossRefGoogle Scholar
  4. 4.
    Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Brandau S, Moses K, Lang S (2013) The kinship of neutrophils and granulocytic myeloid-derived suppressor cells in cancer: cousins, siblings or twins? Semin Cancer Biol 23:171–182PubMedCrossRefGoogle Scholar
  6. 6.
    Bruger AM, Dorhoi A, Esendagli G, Barczyk-Kahlert K, van der Bruggen P, Lipoldova M, Perecko T, Santibanez J, Saraiva M, Van Ginderachter JA, Brandau S (2018) How to measure the immunosuppressive activity of MDSC: assays, problems and potential solutions. Cancer Immunol Immunother.  https://doi.org/10.1007/s00262-018-2170-8 PubMedCrossRefGoogle Scholar
  7. 7.
    Ginhoux F, Jung S (2014) Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 14:392–404PubMedCrossRefGoogle Scholar
  8. 8.
    Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C, de Bruijn MF, Geissmann F, Rodewald HR (2015) Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518:547–551PubMedCrossRefGoogle Scholar
  10. 10.
    Hoeffel G, Chen J, Lavin Y, Low D, Almeida FF, See P, Beaudin AE, Lum J, Low I, Forsberg EC, Poidinger M, Zolezzi F, Larbi A, Ng LG, Chan JK, Greter M, Becher B, Samokhvalov IM, Merad M, Ginhoux F (2015) C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42:665–678PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Ginhoux F, Guilliams M (2016) Tissue-resident macrophage ontogeny and homeostasis. Immunity 44:439–449PubMedCrossRefGoogle Scholar
  12. 12.
    Movahedi K, Van Ginderachter JA (2016) The ontogeny and microenvironmental regulation of tumor-associated macrophages. Antioxid Redox Signal 25:775–791PubMedCrossRefGoogle Scholar
  13. 13.
    Movahedi K, Laoui D, Gysemans C, Baeten M, Stange G, Van den Bossche J, Mack M, Pipeleers D, In’t Veld P, De Baetselier P, Van Ginderachter JA (2010) Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 70:5728–5739PubMedCrossRefGoogle Scholar
  14. 14.
    Shand FH, Ueha S, Otsuji M, Koid SS, Shichino S, Tsukui T, Kosugi-Kanaya M, Abe J, Tomura M, Ziogas J, Matsushima K (2014) Tracking of intertissue migration reveals the origins of tumor-infiltrating monocytes. Proc Natl Acad Sci USA 111:7771–7776PubMedCrossRefGoogle Scholar
  15. 15.
    Tymoszuk P, Evens H, Marzola V, Wachowicz K, Wasmer MH, Datta S, Muller-Holzner E, Fiegl H, Bock G, van Rooijen N, Theurl I, Doppler W (2014) In situ proliferation contributes to accumulation of tumor-associated macrophages in spontaneous mammary tumors. Eur J Immunol 44:2247–2262PubMedCrossRefGoogle Scholar
  16. 16.
    Bowman RL, Klemm F, Akkari L, Pyonteck SM, Sevenich L, Quail DF, Dhara S, Simpson K, Gardner EE, Iacobuzio-Donahue CA, Brennan CW, Tabar V, Gutin PH, Joyce JA (2016) Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies. Cell Rep 17:2445–2459PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Zhu Y, Herndon JM, Sojka DK, Kim KW, Knolhoff BL, Zuo C, Cullinan DR, Luo J, Bearden AR, Lavine KJ, Yokoyama WM, Hawkins WG, Fields RC, Randolph GJ, DeNardo DG (2017) Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47:323–338PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Kiss M, Van Gassen S, Movahedi K, Saeys Y, Laoui D (2018) Myeloid cell heterogeneity in cancer: not a single cell alike. Cell Immunol.  https://doi.org/10.1016/j.cellimm.2018.02.008 PubMedCrossRefGoogle Scholar
  19. 19.
    Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, Cho HI, Celis E, Quiceno DG, Padhya T, McCaffrey TV, McCaffrey JC, Gabrilovich DI (2010) HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 207:2439–2453PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Laoui D, Van Overmeire E, Di Conza G, Aldeni C, Keirsse J, Morias Y, Movahedi K, Houbracken I, Schouppe E, Elkrim Y, Karroum O, Jordan B, Carmeliet P, Gysemans C, De Baetselier P, Mazzone M, Van Ginderachter JA (2014) Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res 74:24–30PubMedCrossRefGoogle Scholar
  21. 21.
    Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter JA, Tamagnone L, Mazzone (2013) Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24:695–709PubMedCrossRefGoogle Scholar
  22. 22.
    Van Overmeire E, Stijlemans B, Heymann F, Keirsse J, Morias Y, Elkrim Y, Brys L, Abels C, Lahmar Q, Ergen C, Vereecke L, Tacke F, De Baetselier P, Van Ginderachter JA, Laoui D (2016) M-CSF and GM-CSF receptor signaling differentially regulate monocyte maturation and macrophage polarization in the tumor microenvironment. Cancer Res 76:35–42PubMedCrossRefGoogle Scholar
  23. 23.
    Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CM, Pryer N, Daniel D, Hwang ES, Rugo HS, Coussens LM (2014) Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26:623–637PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Laoui D, Keirsse J, Morias Y, Van Overmeire E, Geeraerts X, Elkrim Y, Kiss M, Bolli E, Lahmar Q, Sichien D, Serneels J, Scott CL, Boon L, De Baetselier P, Mazzone M, Guilliams M, Van Ginderachter JA (2016) The tumor microenvironment harbors ontogenically distinct dendritic cell populations with opposing effects on tumor immunity. Nat Commun 7:13720PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Han Q, Shi H, Liu F (2016) CD163(+) M2-type tumor-associated macrophage support the suppression of tumor-infiltrating T cells in osteosarcoma. Int Immunopharmacol 34:101–106PubMedCrossRefGoogle Scholar
  26. 26.
    Harney AS, Arwert EN, Entenberg D, Wang Y, Guo P, Qian BZ, Oktay MH, Pollard JW, Jones JG, Condeelis JS (2015) Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov 5:932–943PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Kitamura T, Qian BZ, Soong D, Cassetta L, Noy R, Sugano G, Kato Y, Li J, Pollard JW (2015) CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J Exp Med 212:1043–1059PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Qian BZ, Zhang H, Li J, He T, Yeo EJ, Soong DY, Carragher NO, Munro A, Chang A, Bresnick AR, Lang RA, Pollard JW (2015) FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis. J Exp Med 212:1433–1448PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Nielsen SR, Quaranta V, Linford A, Emeagi P, Rainer C, Santos A, Ireland L, Sakai T, Sakai K, Kim YS, Engle D, Campbell F, Palmer D, Ko JH, Tuveson DA, Hirsch E, Mielgo A, Schmid MC (2016) Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat Cell Biol 18:549–560PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S, Singh S, Williams C, Soplop N, Uryu K, Pharmer L, King T, Bojmar L, Davies AE, Ararso Y, Zhang T, Zhang H, Hernandez J, Weiss JM, Dumont-Cole VD, Kramer K, Wexler LH, Narendran A, Schwartz GK, Healey JH, Sandstrom P, Labori KJ, Kure EH, Grandgenett PM, Hollingsworth MA, de Sousa M, Kaur S, Jain M, Mallya K, Batra SK, Jarnagin WR, Brady MS, Fodstad O, Muller V, Pantel K, Minn AJ, Bissell MJ, Garcia BA, Kang Y, Rajasekhar VK, Ghajar CM, Matei I, Peinado H, Bromberg J, Lyden D (2015) Tumour exosome integrins determine organotropic metastasis. Nature 527:329–335PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Kumagai S, Marumo S, Shoji T, Sakuramoto M, Hirai T, Nishimura T, Arima N, Fukui M, Huang CL (2014) Prognostic impact of preoperative monocyte counts in patients with resected lung adenocarcinoma. Lung Cancer 85:457–464PubMedCrossRefGoogle Scholar
  32. 32.
    Porrata LF, Ristow K, Colgan JP, Habermann TM, Witzig TE, Inwards DJ, Ansell SM, Micallef IN, Johnston PB, Nowakowski GS, Thompson C, Markovic SN (2012) Peripheral blood lymphocyte/monocyte ratio at diagnosis and survival in classical Hodgkin’s lymphoma. Haematologica 97:262–269PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Gwak JM, Jang MH, Kim DI, Seo AN, Park SY (2015) Prognostic value of tumor-associated macrophages according to histologic locations and hormone receptor status in breast cancer. PLoS One 10:e0125728PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Lin CN, Wang CJ, Chao YJ, Lai MD, Shan YS (2015) The significance of the co-existence of osteopontin and tumor-associated macrophages in gastric cancer progression. BMC Cancer 15:128PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Di Caro G, Cortese N, Castino GF, Grizzi F, Gavazzi F, Ridolfi C, Capretti G, Mineri R, Todoric J, Zerbi A, Allavena P, Mantovani A, Marchesi F (2016) Dual prognostic significance of tumour-associated macrophages in human pancreatic adenocarcinoma treated or untreated with chemotherapy. Gut 65:1710–1720PubMedCrossRefGoogle Scholar
  36. 36.
    Lu H, Clauser KR, Tam WL, Fröse J, Ye X, Eaton EN, Reinhardt F, Donnenberg VS, Bhargava R, Carr SA, Weinberg RA (2014) A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol 16:1105–1117PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE, Belaygorod L, Carpenter D, Collins L, Piwnica-Worms D, Hewitt S, Udupi GM, Gallagher WM, Wegner C, West BL, Wang-Gillam A, Goedegebuure P, Linehan DC, DeNardo DG (2013) Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 73:1128–1141PubMedCrossRefGoogle Scholar
  38. 38.
    Ruffell B, Coussens LM (2015) Macrophages and therapeutic resistance in cancer. Cancer Cell 27:462–472PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Kim J, Bae JS (2016) Tumor-associated macrophages and neutrophils in tumor microenvironment. Mediators Inflamm 2016:6058147PubMedPubMedCentralGoogle Scholar
  40. 40.
    Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8:618–631PubMedCrossRefGoogle Scholar
  41. 41.
    De Palma M, Venneri MA, Galli R, Sergi L, Politi LS, Sampaolesi M, Naldini L (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8:211–226PubMedCrossRefGoogle Scholar
  42. 42.
    Turrini R, Pabois A, Xenarios I, Coukos G, Delaloye JF, Doucey MA (2017) TIE-2 expressing monocytes in human cancers. Oncoimmunology 6:e1303585PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Wyckoff J, Wang W, Lin EY, Wang Y, Pixley F, Stanley ER, Graf T, Pollard JW, Segall J, Condeelis J (2004) A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 64:7022–7029PubMedCrossRefGoogle Scholar
  44. 44.
    Wang H, Wang X, Li X, Fan Y, Li G, Guo C, Zhu F, Zhang L, Shi Y (2014) CD68(+)HLA-DR(+) M1-like macrophages promote motility of HCC cells via NF-kappaB/FAK pathway. Cancer Lett 345:91–99PubMedCrossRefGoogle Scholar
  45. 45.
    Chen Q, Zhang XH, Massague J (2011) Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 20:538–549PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Smith HA, Kang Y (2013) The metastasis-promoting roles of tumor-associated immune cells. J Mol Med (Berl) 91:411–429CrossRefGoogle Scholar
  47. 47.
    Kuang DM, Zhao Q, Peng C, Xu J, Zhang JP, Wu C, Zheng L (2009) Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med 206:1327–1337PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Savage ND, de Boer T, Walburg KV, Joosten SA, van Meijgaarden K, Geluk A, Ottenhoff TH (2008) Human anti-inflammatory macrophages induce Foxp3 + GITR + CD25 + regulatory T cells, which suppress via membrane-bound TGFbeta-1. J Immunol 181:2220–2226PubMedCrossRefGoogle Scholar
  49. 49.
    de la Cruz-Merino L, Lejeune M, Nogales Fernández E, Henao Carrasco F, Grueso López A, Illescas Vacas A, Pulla MP, Callau C, Álvaro T (2012) Role of immune escape mechanisms in Hodgkin’s lymphoma development and progression: a whole new world with therapeutic implications. Clin Dev Immunol 2012:756353PubMedPubMedCentralGoogle Scholar
  50. 50.
    Liu WL, Lin YH, Xiao H, Xing S, Chen H, Chi PD, Zhang G (2014) Epstein–Barr virus infection induces indoleamine 2,3-dioxygenase expression in human monocyte-derived macrophages through p38/mitogen-activated protein kinase and NF-kappaB pathways: impairment in T cell functions. J Virol 88:6660–6671PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Beury DW, Parker KH, Nyandjo M, Sinha P, Carter KA, Ostrand-Rosenberg S (2014) Cross-talk among myeloid-derived suppressor cells, macrophages, and tumor cells impacts the inflammatory milieu of solid tumors. J Leukoc Biol 96:1109–1118PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S (2007) Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol 179:977–983PubMedCrossRefGoogle Scholar
  53. 53.
    Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P (2017) Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14:399–416PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Dumitru CA, Gholaman H, Trellakis S, Bruderek K, Dominas N, Gu X, Bankfalvi A, Whiteside TL, Lang S, Brandau S (2011) Tumor-derived macrophage migration inhibitory factor modulates the biology of head and neck cancer cells via neutrophil activation. Int J Cancer 129:859–869PubMedCrossRefGoogle Scholar
  55. 55.
    Sionov RV, Fridlender ZG, Granot Z (2015) The multifaceted roles neutrophils play in the tumor microenvironment. Cancer Microenviron 8:125–158PubMedCrossRefGoogle Scholar
  56. 56.
    Granot Z, Jablonska J (2015) Distinct functions of neutrophil in cancer and its regulation. Mediators Inflamm 2015:701067PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Worthen GS, Albelda SM (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16:183–194PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Strauss L, Sangaletti S, Consonni FM, Szebeni G, Morlacchi S, Totaro MG, Porta C, Anselmo A, Tartari S, Doni A, Zitelli F, Tripodo C, Colombo MP, Sica A (2015) RORC1 regulates tumor-promoting “emergency” granulo-monocytopoiesis. Cancer Cell 28:253–269PubMedCrossRefGoogle Scholar
  59. 59.
    Cortez-Retamozo V, Etzrodt M, Newton A, Rauch PJ, Chudnovskiy A, Berger C, Ryan RJ, Iwamoto Y, Marinelli B, Gorbatov R, Forghani R, Novobrantseva TI, Koteliansky V, Figueiredo JL, Chen JW, Anderson DG, Nahrendorf M, Swirski FK, Weissleder R, Pittet MJ (2012) Origins of tumor-associated macrophages and neutrophils. Proc Natl Acad Sci USA 109:2491–2496PubMedCrossRefGoogle Scholar
  60. 60.
    Jablonska J, Wu CF, Andzinski L, Leschner S, Weiss S (2014) CXCR2-mediated tumor-associated neutrophil recruitment is regulated by IFN-beta. Int J Cancer 134:1346–1358PubMedCrossRefGoogle Scholar
  61. 61.
    Jablonska J, Leschner S, Westphal K, Lienenklaus S, Weiss S (2010) Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. J Clin Invest 120:1151–1164PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Kobayashi Y (2008) The role of chemokines in neutrophil biology. Front Biosci 13:2400–2407PubMedCrossRefGoogle Scholar
  63. 63.
    Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R (2011) Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20:300–314PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Wu CF, Andzinski L, Kasnitz N, Kröger A, Klawonn F, Lienenklaus S, Weiss S, Jablonska J (2015) The lack of type I interferon induces neutrophil-mediated pre-metastatic niche formation in the mouse lung. Int J Cancer 137:837–847PubMedCrossRefGoogle Scholar
  66. 66.
    Cools-Lartigue J, Spicer J, McDonald B, Gowing S, Chow S, Giannias B, Bourdeau F, Kubes P, Ferri L (2013) Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J Clin Invest 123:3446–3458PubMedCentralCrossRefGoogle Scholar
  67. 67.
    Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau CS, Verstegen NJM, Ciampricotti M, Hawinkels LJAC, Jonkers J, de Visser KE (2015) IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522:345–348PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    López-Lago MA, Posner S, Thodima VJ, Molina AM, Motzer RJ, Chaganti RS (2013) Neutrophil chemokines secreted by tumor cells mount a lung antimetastatic response during renal cell carcinoma progression. Oncogene 32:1752–1760PubMedCrossRefGoogle Scholar
  69. 69.
    Brandau S, Dumitru CA, Lang S (2013) Protumor and antitumor functions of neutrophil granulocytes. Semin Immunopathol 35:163–176PubMedCrossRefGoogle Scholar
  70. 70.
    Coffelt SB, Wellenstein MD, de Visser KE (2016) Neutrophils in cancer: neutral no more. Nat Rev Cancer 16:431–446PubMedCrossRefGoogle Scholar
  71. 71.
    Leliefeld PH, Koenderman L, Pillay J (2015) How neutrophils shape adaptive immune responses. Front Immunol 6:471PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Kolaczkowska E, Kubes P (2013) Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 13:159–175PubMedCrossRefGoogle Scholar
  73. 73.
    Dallegri F, Ottonello L (1992) Neutrophil-mediated cytotoxicity against tumour cells: state of art. Arch Immunol Ther Exp (Warsz) 40:39–42Google Scholar
  74. 74.
    van Egmond M, Bakema JE (2013) Neutrophils as effector cells for antibody-based immunotherapy of cancer. Semin Cancer Biol 23:190–199PubMedCrossRefGoogle Scholar
  75. 75.
    Beauvillain C, Delneste Y, Scotet M, Peres A, Gascan H, Guermonprez P, Barnaba V, Jeannin P (2007) Neutrophils efficiently cross-prime naive T cells in vivo. Blood 110:2965–2973PubMedCrossRefGoogle Scholar
  76. 76.
    Kousis PC, Henderson BW, Maier PG, Gollnick SO (2007) Photodynamic therapy enhancement of antitumor immunity is regulated by neutrophils. Cancer Res 67:10501–10510PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Suttmann H, Riemensberger J, Bentien G, Schmaltz D, Stöckle M, Jocham D, Böhle A, Brandau S (2006) Neutrophil granulocytes are required for effective Bacillus Calmette–Guérin immunotherapy of bladder cancer and orchestrate local immune responses. Cancer Res 66:8250–8257PubMedCrossRefGoogle Scholar
  78. 78.
    Albanesi M, Mancardi DA, Jönsson F, Iannascoli B, Fiette L, Di Santo JP, Lowell CA, Bruhns P (2013) Neutrophils mediate antibody-induced antitumor effects in mice. Blood 122:3160–3164PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, Nair VS, Xu Y, Khuong A, Hoang CD, Diehn M, West RB, Plevritis SK, Alizadeh AA (2015) The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med 21:938–945PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Shen M, Hu P, Donskov F, Wang G, Liu Q, Du J (2014) Tumor-associated neutrophils as a new prognostic factor in cancer: A systematic review and meta-analysis. PLoS One 9:e98259PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Suh B, Ahn YO, Kim TM, Lee JO, Lee SH, Heo DS (2012) CD15+/CD16low human granulocytes from terminal cancer patients: granulocytic myeloid-derived suppressor cells that have suppressive function. Tumour Biol 33:121–129PubMedCrossRefGoogle Scholar
  82. 82.
    Schmielau J, Finn OJ (2001) Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of T-cell function in advanced cancer patients. Cancer Res 61:4756–4760PubMedGoogle Scholar
  83. 83.
    Sippel TR, White J, Nag K, Tsvankin V, Klaassen M, Kleinschmidt-DeMasters BK, Waziri A (2011) Neutrophil degranulation and immunosuppression in patients with GBM: restoration of cellular immune function by targeting arginase I. Clin Cancer Res 17:6992–7002PubMedCrossRefGoogle Scholar
  84. 84.
    Bausch D, Pausch T, Krauss T, Hopt UT, Fernandez-del-Castillo C, Warshaw AL, Thayer SP, Keck T (2011) Neutrophil granulocyte derived MMP-9 is a VEGF independent functional component of the angiogenic switch in pancreatic ductal adenocarcinoma. Angiogenesis 14:235–243PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Galdiero MR, Bianchi P, Grizzi F, Di Caro G, Basso G, Ponzetta A, Bonavita E, Barbagallo M, Tartari S, Polentarutti N, Malesci A, Marone G, Roncalli M, Laghi L, Garlanda C, Mantovani A, Jaillon S (2016) Occurrence and significance of tumor-associated neutrophils in patients with colorectal cancer. Int J Cancer 139:446–456PubMedCrossRefGoogle Scholar
  86. 86.
    Tecchio C, Huber V, Scapini P, Calzetti F, Margotto D, Todeschini G, Pilla L, Martinelli G, Pizzolo G, Rivoltini L, Cassatella MA (2004) IFNalpha-stimulated neutrophils and monocytes release a soluble form of TNF-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand) displaying apoptotic activity on leukemic cells. Blood 103:3837–3844PubMedCrossRefGoogle Scholar
  87. 87.
    Scapini P, Marini O, Tecchio C, Cassatella MA (2016) Human neutrophils in the saga of cellular heterogeneity: insights and open questions. Immunol Rev 273:48–60PubMedCrossRefGoogle Scholar
  88. 88.
    Moses K, Brandau (2016) Human neutrophils: Their role in cancer and relation to myeloid-derived suppressor cells. Semin Immunol 28:187–196PubMedCrossRefGoogle Scholar
  89. 89.
    Schmidt H, Bastholt L, Geertsen P, Christensen IJ, Larsen S, Gehl J, von der Maase H (2005) Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: a prognostic model. Br J Cancer 93:273–278PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Eruslanov EB, Bhojnagarwala PS, Quatromoni JG, Stephen TL, Ranganathan A, Deshpande C, Akimova T, Vachani A, Litzky L, Hancock WW, Conejo-Garcia JR, Feldman M, Albelda SM, Singhal S (2014) Tumor-associated neutrophils stimulate T cell resposnses in early-stage human lung cancer. J Clin Invest 124:5466–5480PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Bellocq A, Antoine M, Flahault A, Philippe C, Crestani B, Bernaudin JF, Mayaud C, Milleron B, Baud L, Cadranel J (1998) Neutrophil alveolitis in bronchioloalveolar carcinoma: induction by tumor-derived interleukin-8 and relation to clinical outcome. Am J Pathol 152:83–92PubMedPubMedCentralGoogle Scholar
  92. 92.
    Templeton AJ, McNamara MG, Šeruga B, Vera-Badillo FE, Aneja P, Ocaña A, Leibowitz-Amit R, Sonpavde G, Knox JJ, Tran B, Tannock IF, Amir E (2014) Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst 106:dju124PubMedCrossRefGoogle Scholar
  93. 93.
    Jensen HK, Donskov F, Marcussen N, Nordsmark M, Lundbeck F, von der Maase H (2009) Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J Clin Oncol 27:4709–4717PubMedCrossRefGoogle Scholar
  94. 94.
    Ilie M, Hofman V, Ortholan C, Bonnetaud C, Coëlle C, Mouroux J, Hofman P (2012) Predictive clinical outcome of the intratumoral CD66b-positive neutrophil-to-CD8-positive T-cell ratio in patients with resectable nonsmall cell lung cancer. Cancer 118:1726–1737PubMedCrossRefGoogle Scholar
  95. 95.
    Jensen TO, Schmidt H, Møller HJ, Donskov F, Høyer M, Sjoegren P, Christensen IJ, Steiniche T (2012) Intratumoral neutrophils and plasmacytoid dendritic cells indicate poor prognosis and are associated with pSTAT3 expression in AJCC stage I/II melanoma. Cancer 118:2476–2485PubMedCrossRefGoogle Scholar
  96. 96.
    Tabariès S, Ouellet V, Hsu BE, Annis MG, Rose AA, Meunier L, Carmona E, Tam CE, Mes-Masson AM, Siegel PM (2015) Granulocytic immune infiltrates are essential for the efficient formation of breast cancer liver metastases. Breast Cancer Res 17:45PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Wislez M, Rabbe N, Marchal J, Milleron B, Crestani B, Mayaud C, Antoine M, Soler P, Cadranel J (2003) Hepatocyte growth factor production by neutrophils infiltrating bronchioloalveolar subtype pulmonary adenocarcinoma: role in tumor progression and death. Cancer Res 63:1405–1412PubMedGoogle Scholar
  98. 98.
    Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182:4499–4506PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12:253–268PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Kanterman J, Sade-Feldman M, Baniyash M (2012) New insights into chronic inflammation-induced immunosuppression. Semin Cancer Biol 22:307–318PubMedCrossRefGoogle Scholar
  101. 101.
    Umansky V, Sevko A (2012) Overcoming immunosuppression in the melanoma microenvironment induced by chronic inflammation. Cancer Immunol Immunother 61:275–282PubMedCrossRefGoogle Scholar
  102. 102.
    Parker KH, Beury DW, Ostrand-Rosenberg S (2015) Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res 128:95–139PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S, Rodriguez PC, Sica A, Umansky V, Vonderheide RH, Gabrilovich DI (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7:12150PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H, Lehner F, Manns MP, Greten TF, Korangy F (2009) Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50:799–807PubMedCrossRefGoogle Scholar
  105. 105.
    Filipazzi P, Huber V, Rivoltini L (2012) Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother 61:255–263PubMedCrossRefGoogle Scholar
  106. 106.
    Poschke I, Kiessling R (2012) On the armament and appearances of human myeloid-derived suppressor cells. Clin Immunol 144:250–268PubMedCrossRefGoogle Scholar
  107. 107.
    Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V (2014) Myeloid-derived suppressor cell heterogeneity in human cancers. Ann NY Acad Sci 1319:47–65PubMedCrossRefGoogle Scholar
  108. 108.
    Gabrilovich DI (2017) Myeloid-derived suppressor cells. Cancer Immunol Res 5:3–8PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Marvel D, Gabrilovich DI (2015) Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest 125:3356–3364PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Su Z, Ni P, Zhou C, Wang J (2016) Myeloid-derived suppressor cells in cancers and inflammatory diseases: angel or demon? Scand J Immunol 84:255–261PubMedCrossRefGoogle Scholar
  111. 111.
    Lang S, Bruderek K, Kaspar C, Höing O, Dominas N, Hussain T, Droege F, Eyth C, Hadaschik B, Brandau S (2018) Clinical relevance and suppressive capacity of human MDSC subsets. Clin Cancer Res.  https://doi.org/10.1158/1078-0432.CCR-17-3726 CrossRefPubMedGoogle Scholar
  112. 112.
    Pan PY, Ma G, Weber KJ, Ozao-Choy J, Wang G, Yin B, Divino CM, Chen SH (2010) Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res 70:99–108PubMedCrossRefGoogle Scholar
  113. 113.
    Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Krüger 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 135:234–243PubMedCrossRefGoogle Scholar
  114. 114.
    Obermajer N, Wong JL, Edwards RP, Chen K, Scott M, Khader S, Kolls JK, Odunsi K, Billiar TR, Kalinski P (2013) Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling. J Exp Med 210:1433–1445PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Novitskiy SV, Pickup MW, Gorska AE, Owens P, Chytil A, Aakre M, Wu H, Shyr Y, Moses HL (2011) TGF-β receptor II loss promotes mammary carcinoma progression by Th17 dependent mechanisms. Cancer Discov 1:430–441PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Kumar V, Cheng P, Condamine T, Mony S, Languino LR, McCaffrey JC, Hockstein N, Guarino M, Masters G, Penman E, Denstman F, Xu X, Altieri DC, Du H, Yan C, Gabrilovich DI (2016) CD45 phosphatase inhibits STAT3 transcription factor activity in myeloid cells and promotes tumor-associated macrophage differentiation. Immunity 44:303–315PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Hu CE, Gan J, Zhang RD, Cheng YR, Huang GJ (2011) Up-regulated myeloid-derived suppressor cell contributes to hepatocellular carcinoma development by impairing dendritic cell function. Scand J Gastroenterol 46:156–164PubMedCrossRefGoogle Scholar
  118. 118.
    Zhang B, Wang Z, Wu L, Zhang M, Li W, Ding J, Zhu J, Wei H, Zhao K (2013) Circulating and tumor-infiltrating myeloid-derived suppressor cells in patients with colorectal carcinoma. PLoS One 8:e57114PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Poschke I, Mao Y, Adamson L, Salazar-Onfray F, Masucci G, Kiessling R (2012) Myeloid-derived suppressor cells impair the quality of dendritic cell vaccines. Cancer Immunol Immunother 61:827–838PubMedCrossRefGoogle Scholar
  120. 120.
    Solito S, Falisi E, Diaz-Montero CM, Doni A, Pinton L, Rosato A, Francescato S, Basso G, Zanovello P, Onicescu G, Garrett-Mayer E, Montero AJ, Bronte V, Mandruzzato S (2011) A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood 118:2254–2265PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Jordan KR, Amaria RN, Ramirez O, Callihan EB, Gao D, Borakove M, Manthey E, Borges VF, McCarter MD (2013) Myeloid-derived suppressor cells are associated with disease progression and decreased overall survival in advanced-stage melanoma patients. Cancer Immunol Immunother 62:1711–1722PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Pico de Coaña Y, Poschke I, Gentilcore G, Mao Y, Nyström M, Hansson J, Masucci GV, Kiessling R (2013) Ipilimumab treatment results in an early decrease in the frequency of circulating granulocytic myeloid-derived suppressor cells as well as their Arginase1 production. Cancer Immunol Res 1:158–162PubMedCrossRefGoogle Scholar
  123. 123.
    Weide B, Martens A, Zelba H, Derhovanessian E, Bailur JK, Kyzirakos C, Pflugfelder A, Eigentler TK, Di Giacomo AM, Maio M, Aarntzen EH, de Vries J, Sucker A, Schadendorf D, Büttner P, Garbe C, Pawelec G (2014) Myeloid-derived suppressor cells predict survival of advanced melanoma patients: comparison with regulatory T cells and NY-ESO-1- or Melan-A-specific T cells. Clin Cancer Res 20:1601–1609PubMedCrossRefGoogle Scholar
  124. 124.
    Condamine T, Dominguez GA, Youn JI, Kossenkov AV, Mony S, Alicea-Torres K, Tcyganov E, Hashimoto A, Nefedova Y, Lin C, Partlova S, Garfall A, Vogl DT, Xu X, Knight SC, Malietzis G, Lee GH, Eruslanov E, Albelda SM, Wang X, Mehta JL, Bewtra M, Rustgi A, Hockstein N, Witt R, Masters G, Nam B, Smirnov D, Sepulveda MA, Gabrilovich DI (2016) Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci Immunol.  https://doi.org/10.1126/sciimmunol.aaf8943 PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Elliot LA, Doherty GA, Sheahan K, Ryan EJ (2017) Human tumor-infiltrating myeloid cells: phenotypic and functional diversity. Front Immunol 8:86.  https://doi.org/10.3389/fimmu.2017.00086 CrossRefGoogle Scholar
  126. 126.
    Zhang H, Li ZL, Ye SB, Ouyang LY, Chen YS, He J, Huang HQ, Zeng YX, Zhang XS, Li J (2015) Myeloid-derived suppressor cells inhibit T cell proliferation in human extranodal NK/T cell lymphoma: a novel prognostic indicator. Cancer Immunol Immunother 64:1587–1599PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Cai TT, Ye SB, Liu YN, He J, Chen QY, Mai HQ, Zhang CX, Cui J, Zhang XS, Busson P, Zeng YX, Li J (2017) LMP1-mediated glycolysis induces myeloid-derived suppressor cell expansion in nasopharyngeal carcinoma. PLoS Pathog 13:e1006503PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Jiang H, Gebhardt C, Umansky L, Beckhove P, Schulze TJ, Utikal J, Umansky V (2015) Elevated chronic inflammatory factors and myeloid-derived suppressor cells indicate poor prognosis in advanced melanoma patients. Int J Cancer 136:2352–2360PubMedCrossRefGoogle Scholar
  129. 129.
    Romano A, Parrinello NL, Vetro C, Forte S, Chiarenza A, Figuera A, Motta G, Palumbo GA, Ippolito M, Consoli U, Di Raimondo F (2015) Circulating myeloid-derived suppressor cells correlate with clinical outcome in Hodgkin Lymphoma patients treated up-front with a risk-adapted strategy. Br J Haematol 168:689–700PubMedCrossRefGoogle Scholar
  130. 130.
    Sade-Feldman M, Kanterman J, Klieger Y, Ish-Shalom E, Olga M, Saragovi A, Shtainberg H, Lotem M, Baniyash M (2016) Clinical significance of circulating CD33+ CD11b+ HLA-DR− myeloid cells in patients with stage IV melanoma treated with ipilimumab. Clin Cancer Res 22:5661–5672PubMedCrossRefGoogle Scholar
  131. 131.
    Gebhardt C, Sevko A, Jiang H, Lichtenberger R, Reith M, Tarnanidis K, Holland-Letz T, Umansky L, Beckhove P, Sucker A, Schadendorf D, Utikal J, Umansky V (2015) Myeloid cells and related chronic inflammatory factors as novel predictive markers in melanoma treatment with ipilimumab. Clin Cancer Res 21:5453–5459PubMedCrossRefGoogle Scholar
  132. 132.
    Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, Matrisian LM, Carbone DP, Lin PC (2004) Expansion of myeloid immune suppressor Gr+ CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6:409–421PubMedCrossRefGoogle Scholar
  133. 133.
    Toh B, Wang X, Keeble J, Sim WJ, Khoo K, Wong WC, Kato M, Prevost-Blondel A, Thiery JP, Abastado JP (2011) Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLoS Biol 9:e1001162PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Kao J, Ko EC, Eisenstein S, Sikora AG, Fu S, Chen SH (2011) Targeting immune suppressing myeloid-derived suppressor cells in oncology. Crit Rev Oncol Hematol 77:12–19PubMedCrossRefGoogle Scholar
  135. 135.
    De Sanctis F, Solito S, Ugel S, Molon B, Bronte V, Marigo I (2016) MDSCs in cancer: conceiving new prognostic and therapeutic targets. Biochim Biophys Acta 1865:35–48PubMedGoogle Scholar
  136. 136.
    Umansky V, Blattner C, Fleming V, Hu X, Gebhardt C, Altevogt P, Utikal J (2017) Myeloid-derived suppressor cells and tumor escape from immune surveillance. Semin Immunopathol 39:295–305PubMedCrossRefGoogle Scholar
  137. 137.
    Guilliams M, Ginhoux F, Jakubzick C, Naik SH, Onai N, Schraml BU, Segura E, Tussiwand R, Yona S (2014) Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol 14:571–578PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Ueno H, Palucka AK, Banchereau J (2010) The expanding family of dendritic cell subsets. Nat Biotechnol 28:813–815PubMedCrossRefGoogle Scholar
  139. 139.
    Veglia F, Gabrilovich DI (2017) Dendritic cells in cancer: the role revisited. Curr Opin Immunol 45:43–51PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Gabrilovich D (2004) Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 4:941–952PubMedCrossRefGoogle Scholar
  141. 141.
    Tang M, Diao J, Gu H, Khatri I, Zhao J, Cattral MS (2015) Toll-like receptor 2 activation promotes tumor dendritic cell dysfunction by regulating IL-6 and IL-10 receptor signaling. Cell Rep 13:2851–2864PubMedCrossRefGoogle Scholar
  142. 142.
    Pinzon-Charry A, Maxwell T, Lopez JA (2005) Dendritic cell dysfunction in cancer: a mechanism for immunosuppression. Immunol Cell Biol 83:451–461PubMedCrossRefGoogle Scholar
  143. 143.
    Herber DL, Cao W, Nefedova Y, Novitskiy SV, Nagaraj S, Tyurin VA, Corzo A, Cho HI, Celis E, Lennox B, Knight SC, Padhya T, McCaffrey TV, McCaffrey JC, Antonia S, Fishman M, Ferris RL, Kagan VE, Gabrilovich DI (2010) Lipid accumulation and dendritic cell dysfunction in cancer. Nat Med 16:880–886PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Ramakrishnan R, Tyurin VA, Veglia F, Condamine T, Amoscato A, Mohammadyani D, Johnson JJ, Zhang LM, Klein-Seetharaman J, Celis E, Kagan VE, Gabrilovich DI (2014) Oxidized lipids block antigen cross-presentation by dendritic cells in cancer. J Immunol 192:2920–2931PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Andzinski L, Kasnitz N, Stahnke S, Wu CF, Gereke M, von Köckritz-Blickwede M, Schilling B, Brandau S, Weiss S, Jablonska J (2016) Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human. Int J Cancer 138:1982–1993PubMedCrossRefGoogle Scholar
  146. 146.
    Andzinski L, Spanier J, Kasnitz N, Kröger A, Jin L, Brinkmann MM, Kalinke U, Weiss S, Jablonska J, Lienenklaus S (2016) Growing tumors induce a local STING dependent Type I IFN response in dendritic cells. Int J Cancer 139:1350–1357PubMedCrossRefGoogle Scholar
  147. 147.
    Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MY, Duggan R, Wang Y, Barber GN, Fitzgerald KA, Alegre ML, Gajewski TF (2014) STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41:830–842PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Zoglmeier C, Bauer H, Nörenberg D, Wedekind G, Bittner P, Sandholzer N, Rapp M, Anz D, Endres S, Bourquin C (2011) CpG blocks immunosuppression by myeloid-derived suppressor cells in tumor-bearing mice. Clin Cancer Res 17:1765–1775PubMedCrossRefGoogle Scholar
  149. 149.
    U’Ren L, Guth A, Kamstock D, Dow S (2010) Type I interferons inhibit the generation of tumor-associated macrophages. Cancer Immunol Immunother 59:587–598PubMedCrossRefGoogle Scholar
  150. 150.
    Steding CE, Wu ST, Zhang Y, Jeng MH, Elzey BD, Kao C (2011) The role of interleukin-12 on modulating myeloid-derived suppressor cells, increasing overall survival and reducing metastasis. Immunology 133:221–238PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Watkins SK, Egilmez NK, Suttles J, Stout RD (2007) IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo. J Immunol 178:1357–1362PubMedCrossRefGoogle Scholar
  152. 152.
    Mantovani A, Allavena P (2015) The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med 212:435–445PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Bazzoni F, Tamassia N, Rossato M, Cassatella MA (2010) Understanding the molecular mechanisms of the multifaceted IL-10-mediated anti-inflammatory response: lessons from neutrophils. Eur J Immunol 40:2360–2368PubMedCrossRefGoogle Scholar
  154. 154.
    Spranger S, Dai D, Horton B, Gajewski TF (2017) Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31:711–723PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Ma Y, Shurin GV, Peiyuan Z, Shurin MR (2013) Dendritic cells in the cancer microenvironment. J Cancer 4:36–44PubMedCrossRefGoogle Scholar
  156. 156.
    Broz ML, Binnewies M, Boldajipour B, Nelson AE, Pollack JL, Erle DJ, Barczak A, Rosenblum MD, Daud A, Barber DL, Amigorena S, Van’t Veer LJ, Sperling AI, Wolf DM, Krummel MF (2014) Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26:638–652PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Sluijter BJ, van den Hout MF, Koster BD, van Leeuwen PA, Schneiders FL, van de Ven R, Molenkamp BG, Vosslamber S, Verweij CL, van den Tol MP, van den Eertwegh AJ, Scheper RJ, de Gruijl TD (2015) Arming the melanoma sentinel lymph node through local administration of CpG-B and GM-CSF: recruitment and activation of BDCA3/CD141(+) dendritic cells and enhanced cross-presentation. Cancer Immunol Res 3:495–505PubMedCrossRefGoogle Scholar
  158. 158.
    Bharadwaj U, Li M, Zhang R, Chen C, Yao Q (2007) Elevated interleukin-6 and G-CSF in human pancreatic cancer cell conditioned medium suppress dendritic cell differentiation and activation. Cancer Res 67:5479–5488PubMedCrossRefGoogle Scholar
  159. 159.
    Michielsen AJ, O’Sullivan JN, Ryan EJ (2012) Tumor conditioned media from colorectal cancer patients inhibits dendritic cell maturation. Oncoimmunology 1:751–753PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Macri C, Dumont C, Johnston AP, Mintern JD (2016) Targeting dendritic cells: a promising strategy to improve vaccine effectiveness. Clin Transl Immunology 5:e66PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Kitamura H, Ohno Y, Toyoshima Y, Ohtake J, Homma S, Kawamura H, Takahashi N, Taketomi A (2017) Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy. Cancer Sci 108:1947–1952PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Andersen MH (2014) The targeting of immunosuppressive mechanisms in hematological malignancies. Leukemia 28:1784–1792PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Viktor Umansky
    • 1
    • 2
  • Gosse J. Adema
    • 3
  • Jaroslaw Baran
    • 4
  • Sven Brandau
    • 5
  • Jo A. Van Ginderachter
    • 6
    • 7
  • Xiaoying Hu
    • 1
    • 2
  • Jadwiga Jablonska
    • 5
  • Slavko Mojsilovic
    • 8
  • Helen A. Papadaki
    • 9
  • Yago Pico de Coaña
    • 10
  • Kim C. M. Santegoets
    • 3
  • Juan F. Santibanez
    • 11
    • 12
  • Karine Serre
    • 13
  • Yu Si
    • 5
  • Isabela Sieminska
    • 4
  • Maria Velegraki
    • 9
  • Zvi G. Fridlender
    • 14
  1. 1.Skin Cancer Unit (G300)German Cancer Research Center (DKFZ)HeidelbergGermany
  2. 2.Department of Dermatology, Venereology and Allergology, University Medical Center MannheimRuprecht Karl University of HeidelbergMannheimGermany
  3. 3.Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical CenterRadboud Institute for Molecular Life SciencesNijmegenThe Netherlands
  4. 4.Department of Clinical Immunology, Institute of PaediatricsJagiellonian University Medical CollegeKrakówPoland
  5. 5.Department of Otorhinolaryngology, University Hospital EssenUniversity Duisburg-EssenEssenGermany
  6. 6.Lab of Cellular and Molecular ImmunologyVrije Universiteit BrusselBrusselsBelgium
  7. 7.Myeloid Cell Immunology LabVIB Center for Inflammation ResearchBrusselsBelgium
  8. 8.Laboratory for Experimental Hematology and Stem Cells, Institute for Medical ResearchUniversity of BelgradeBelgradeRepublic of Serbia
  9. 9.Department of Hematology, School of MedicineUniversity of CreteHeraklionGreece
  10. 10.Department of Oncology and PathologyKarolinska InstitutetStockholmSweden
  11. 11.Department of Molecular Oncology, Institute for Medical ResearchUniversity of BelgradeBelgradeRepublic of Serbia
  12. 12.Centro Integrativo de Biología y Química Aplicada (CIBQA)Universidad Bernardo O’HigginsSantiagoChile
  13. 13.Faculty of Medicine, Institute of Molecular Medicine (IMM)-João Lobo AntunesUniversity of LisbonLisbonPortugal
  14. 14.Institute of Pulmonary MedicineHadassah-Hebrew University Medical CenterJerusalemIsrael

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