Myeloid-derived suppressor cells and tumor escape from immune surveillance

Seminars in Immunopathology

Volumn 39, Issue 3, 2017, Pages 295-305

  Umansky, Viktor ^a,b   Blattner, Carolin ^a,b   Fleming, Viktor ^a,b   Hu, Xiaoying ^a,b   Gebhardt, Christoffer ^a,b   Altevogt, Peter ^a,b   Utikal, Jochen ^a,b  

^a GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

^b UNIVERSITY OF HEIDELBERG   (Germany)

Author keywords

Cancer; Chronic inflammatory factors; Extracellular microvesicles; Immunosuppression; Myeloid derived suppressor cells; Tumor microenvironment

Indexed keywords

CARCINOGENESIS; CELL ACTIVATION; CELL DIFFERENTIATION; CELL EXPANSION; CELL FUNCTION; CELL RECRUITMENT; EXOSOME; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; IMMUNOSURVEILLANCE; IN VITRO STUDY; METASTASIS; MYELOID-DERIVED SUPPRESSOR CELL; MYELOPOIESIS; NATURAL KILLER CELL; NONHUMAN; REVIEW; T LYMPHOCYTE; TUMOR ESCAPE; TUMOR GROWTH; TUMOR MICROENVIRONMENT; ANIMAL; CELL MOTION; CYTOLOGY; IMMUNOLOGY; MEMBRANE MICROPARTICLE; METABOLISM; NEOPLASM; PATHOLOGY; SIGNAL TRANSDUCTION;

AUTACOID; CYTOKINE;

ANIMALS; CELL DIFFERENTIATION; CELL MOVEMENT; CELL-DERIVED MICROPARTICLES; CYTOKINES; EXTRACELLULAR VESICLES; HUMANS; IMMUNOLOGIC SURVEILLANCE; IMMUNOSUPPRESSION; INFLAMMATION MEDIATORS; MYELOID-DERIVED SUPPRESSOR CELLS; NEOPLASMS; SIGNAL TRANSDUCTION; TUMOR ESCAPE; TUMOR MICROENVIRONMENT;

EID: 84992690893     PISSN: 18632297     EISSN: 18632300     Source Type: Journal    
DOI: 10.1007/s00281-016-0597-6     Document Type: Review

References (109)

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 27:8–15
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 14:135–146
3. Lesokhin AM, Callahan MK, Postow MA, Wolchok JD (2015) On being less tolerant: enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation. Sci Transl Med 7:280 sr1
4. Fridman WH, Pagès F, Sautès-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12:298–306
5. Melief CJ, van Hall T, Arens R, Ossendorp F, van der Burg SH (2015) Therapeutic cancer vaccines. J Clin Invest 125:3401–3412
6. Yang JC, Rosenberg SA (2016) Adoptive T-cell therapy for cancer. Adv Immunol 130:279–294
7. Postow MA, Callahan MK, Wolchok JD (2015) Immune checkpoint blockade in cancer therapy. J Clin Oncol 33:1974–1982
8. 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 21:5453–5459
9. Stadler S, Weina K, Gebhardt C, Utikal J (2015) New therapeutic options for advanced non-resectable malignant melanoma. Adv Med Sci 60:83–88
10. Zimmer L, Eigentler TK, Kiecker F, Simon J, Utikal J, Mohr P, Berking C, Kämpgen E, Dippel E, Stadler R, Hauschild A, Fluck M, Terheyden P, Rompel R, Loquai C, Assi Z, Garbe C, Schadendorf D (2015) Open-label, multicenter, single-arm phase II DeCOG-study of ipilimumab in pretreated patients with different subtypes of metastatic melanoma. J Transl Med 13:351
11. Garrido F, Algarra I, García-Lora AM (2010) The escape of cancer from T lymphocytes: immunoselection of MHC class I loss variants harboring structural-irreversible "hard" lesions. Cancer Immunol Immunother 59:1601–1606
12. Bedognetti D, Hendrickx W, Ceccarelli M, Miller LD, Seliger B (2016) Disentangling the relationship between tumor genetic programs and immune responsiveness. Curr Opin Immunol 39:150–158
13. Parmiani G, Castelli C, Santinami M, Rivoltini L (2007) Melanoma immunology: past, present and future. Curr Opin Oncol 19:121–127
14. Ostrand-Rosenberg S (2008) Immune surveillance: a balance between protumor and antitumor immunity. Curr Opin Genet Dev 18:11–18
15. Nishikawa H, Sakaguchi S (2014) Regulatory T cells in cancer immunotherapy. Curr Opin Immunol 27:1–7
16. Tan TT, Coussens LM (2007) Humoral immunity, inflammation and cancer. Curr Opin Immunol 19:209–216
17. Biswas SK, Allavena P, Mantovani A (2013) Tumor-associated macrophages: functional diversity, clinical significance, and open questions. Semin Immunopathol 35:585–600
18. Lewis CE, De Palma M, Naldini L (2007) Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res 67:8429–8432
19. Fridlender ZG, Albelda SM (2012) Tumor-associated neutrophils: friend or foe? Carcinogenesis 33:949–955
20. Zhong H, Gutkin DW, Han B, Ma Y, Keskinov AA, Shurin MR, Shurin GV (2014) Origin and pharmacological modulation of tumor-associated regulatory dendritic cells. Int J Cancer 134:2633–2645
21. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12:253–268
22. 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 1865:35–48
23. Parker KH, Beury DW, Ostrand-Rosenberg S (2015) Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res 128:95–139
24. Kumar V, Patel S, Tcyganov E, Gabrilovich DI (2016) The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol 37:208–220
25. Meirow Y, Kanterman J, Baniyash M (2015) Paving the road to tumor development and spreading: myeloid-derived suppressor cells are ruling the fate. Front Immunol 6:523
26. Ostrand-Rosenberg S (2010) Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 59:1593–1600
27. 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 7:12150
28. Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V (2014) Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci 1319:47–65
29. Filipazzi P, Huber V, Rivoltini L (2012) Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother 61:255–263
30. Kanterman J, Sade-Feldman M, Baniyash M (2012) New insights into chronic inflammation-induced immunosuppression. Semin Cancer Biol 22:307–318
31. Umansky V, Sevko A (2012) Melanoma-induced immunosuppression and its neutralization. Semin Cancer Biol 22:319–326
32. Umansky V, Sevko A, Gebhardt C, Utikal J (2014) Myeloid-derived suppressor cells in malignant melanoma. J Dtsch Dermatol Ges 12:1021–1027
33. Katanov C, Lerrer S, Liubomirski Y, Leider-Trejo L, Meshel T, Bar J, Feniger-Barish R, Kamer I, Soria-Artzi G, Kahani H, Banerjee D, Ben-Baruch A (2015) Regulation of the inflammatory profile of stromal cells in human breast cancer: prominent roles for TNF-α and the NF-κB pathway. Stem Cell Res Ther 6:87
34. Thery C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2:569–579
35. Filipazzi P, Bürdek M, Villa A, Rivoltini L, Huber V (2012) Recent advances on the role of tumor exosomes in immunosuppression and disease progression. Semin Cancer Biol 22:342–349
36. Whiteside TL (2016) Exosomes and tumor-mediated immune suppression. J Clin Invest 126:1216–1223
37. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809
38. Sade-Feldman M, Kanterman J, Ish-Shalom E, Elnekave M, Horwitz E, Baniyash M (2013) Tumor necrosis factor-alpha blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation. Immunity 38:541–554
39. Gasteiger G, Rudensky AY (2014) Interactions between innate and adaptive lymphocytes. Nat Rev Immunol 14:631–639
40. Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, Schreiber RD (1998) Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A 95:7556–7561
41. Zaidi MR, Merlino G (2011) The two faces of interferon-γ in cancer. Clin Cancer Res 17:6118–6124
42. Raber P, Ochoa AC, Rodríguez PC (2012) Metabolism of L-arginine by myeloid-derived suppressor cells in cancer: mechanisms of T cell suppression and therapeutic perspectives. Immunol Investig 41:614–634
43. Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S (2010) Myeloid-derived suppressor cells inhibit T-cell activation by depleting cysteine and cysteine. Cancer Res 70:68–77
44. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V, Chouaib S (2014) PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 211:781–790
45. Gajewski TF, Woo SR, Zha Y, Spaapen R, Zheng Y, Corrales L, Spranger S (2013) Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol 25:268–276
46. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF (2013) Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med 5:200ra116
47. Noman MZ, Janji B, Hu S, Wu JC, Martelli F, Bronte V, Chouaib S Tumor-promoting effects of myeloid-derived suppressor cells are potentiated by hypoxia-induced expression of miR-210. Cancer Res 75:3771–3787
48. 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 207:2439–2453
49. Sitkovsky MV, Hatfield S, Abbott R, Belikoff B, Lukashev D, Ohta A (2014) Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists. Cancer Immunol Res 2:598–605
50. Umansky V, Shevchenko I, Bazhin AV, Utikal J (2014) Extracellular adenosine metabolism in immune cells in melanoma. Cancer Immunol Immunother 63:1073–1080
51. Pickup M, Novitskiy S, Moses HL (2013) The roles of TGFβ in the tumour microenvironment. Nat Rev Cancer 13:788–799
52. Regateiro FS, Howie D, Nolan KF, Agorogiannis EI, Greaves DR, Cobbold SP, Waldmann H (2011) Generation of anti-inflammatory adenosine by leukocytes is regulated by TGF-beta. Eur J Immunol 41:2955–2965
53. Junger WG (2011) Immune cell regulation by autocrine purinergic signalling. Nat Rev Immunol 11:201–212
54. Ryzhov S, Novitskiy SV, Goldstein AE, Biktasova A, Blackburn MR, Biaggioni I, Dikov MM, Feoktistov I (2011) Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b + Gr1+ cells. J Immunol 187:6120–6129
55. Bogdan C (2001) Nitric oxide and the immune response. Nat Immunol 2:907–916
56. Molon B, Ugel S, Del Pozzo F (2011) Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med 208:1949–1962
57. Sebens Müerköster S, Werbing V, Sipos B, Debus MA, Witt M, Grossmann M, Leisner D, Kötteritzsch J, Kappes H, Klöppel G, Altevogt P, Fölsch UR, Schäfer H (2007) Drug-induced expression of the cellular adhesion molecule L1CAM confers anti-apoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells. Oncogene 26:2759–2768
58. Tartour E, Pere H, Maillere B, Terme M, Merillon N, Taieb J, Sandoval F, Quintin-Colonna F, Lacerda K, Karadimou A, Badoual C, Tedgui A, Fridman WH, Oudard S (2011) Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev 30:83–95
59. Qu P, Yan C, Du H (2011) Matrix metalloproteinase 12 overexpression in myeloid lineage cells plays a key role in modulating myelopoiesis, immune suppression, and lung tumorigenesis. Blood 117:4476–4489
60. 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 70:99–108
61. Sevko A, Sade-Feldman M, Kanterman J, Michels T, Falk CS, Umansky L, Ramacher M, Kato M, Schadendorf D, Baniyash M, Umansky V (2013) Cyclophosphamide promotes chronic inflammation-dependent immunosuppression and prevents antitumor response in melanoma. J Invest Dermatol 133:1610–1619
62. Meyer C, Sevko A, Ramacher M, Bazhin AV, Falk CS, Osen W, Borrello I, Kato M, Schadendorf D, Baniyash M, Umansky V (2011) Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model. Proc Natl Acad Sci USA 108:17111–17116
63. Sevko A, Michels T, Vrohlings M, Umansky L, Beckhove P, Kato M, Shurin GV, Shurin MR, Umansky V (2013) Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model. J Immunol 190:2464–2471
64. Mikyšková R, Indrová M, Polláková V, Bieblová J, Símová J, Reiniš M (2012) Cyclophosphamide-induced myeloid-derived suppressor cell population is immunosuppressive but not identical to myeloid-derived suppressor cells induced by growing TC-1 tumors. J Immunother 35:374–384
65. Schulz O, Hammerschmidt SI, Moschovakis GL, Förster R (2016) Chemokines and chemokine receptors in lymphoid tissue dynamics. Annu Rev Immunol 34:203–242
66. Homey B, Muller A, Zlotnik A (2002) Chemokines: agents for the immunotherapy of cancer? Nature Rev Immunol 2:175–184
67. Lesokhin AM, Hohl TM, Kitano S, Cortez C, Hirschhorn-Cymerman D, Avogadri F, Rizzuto GA, Lazarus JJ, Pamer EG, Houghton AN, Merghoub T, Wolchok JD (2012) Monocytic CCR2(+) myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment. Cancer Res 72:876–886
68. Izhak L, Wildbaum G, Weinberg U, Shaked Y, Alami J, Dumont D, Friedman B, Stein A, Karin N (2010) Predominant expression of CCL2 at the tumor site of prostate cancer patients directs a selective loss of immunological tolerance to CCL2 that could be amplified in a beneficial manner. J Immunol 184:1092–1101
69. Izhak L, Wildbaum G, Jung S, Stein A, Shaked Y, Karin N (2012) Dissecting the autocrine and paracrine roles of the CCR2-CCL2 axis in tumor survival and angiogenesis. PLoS One 7:e28305
70. Van Deventer HW, O’Connor W Jr, Brickey WJ, Aris RM, Ting JP, Serody JS (2005) C-C chemokine receptor 5 on stromal cells promotes pulmonary metastasis. Cancer Res 65:3374–3379
71. Halama N, Zoernig I, Berthel A, Kahlert C, Klupp F, Suarez-Carmona M, Suetterlin T, Brand K, Krauss J, Lasitschka F, Lerchl T, Luckner-Minden C, Ulrich A, Koch M, Weitz J, Schneider M, Buechler MW, Zitvogel L, Herrmann T, Benner A, Kunz C, Luecke S, Springfeld C, Grabe N, Falk CS, Jaeger D (2016) Tumoral immune cell exploitation in colorectal cancer metastases can Be targeted effectively by anti-CCR5 therapy in cancer patients. Cancer Cell 29:587–601
72. Balistreri CR, Carruba G, Calabro M, Campisi I, Di Carlo D, Lio D, Colonna-Romano G, Candore G, Caruso C (2009) CCR5 proinflammatory allele in prostate cancer risk: a pilot study in patients and centenarians from Sicily. Ann N Y Acad Sci 1155:289–292
73. Span PN, Pollakis G, Paxton WA, Sweep FC, Foekens J, Martens JW, Sieuwerts AM, van Laarhoven HW (2015) Improved metastasis-free survival in nonadjuvantly treated postmenopausal breast cancer patients with chemokine receptor 5 del32 frame shift mutations. Int J Cancer 136:91–97
74. Ng-Cashin J, Kuhns JJ, Burkett SE, Powderly JD, Craven RR, van Deventer HW, Kirby SL, Serody JS (2003) Host absence of CCR5 potentiates dendritic cell vaccination. J Immunol 170:4201–4208
75. Kato M, Takahashi M, Akhand AA, Liu W, Dai Y, Shimizu S, Iwamoto T, Suzuki H, Nakashima I (1998) Transgenic mouse model for skin malignant melanoma. Oncogene 17:1885–1888
76. Eng C (1999) RET proto-oncogene in the development of human cancer. J Clin Oncol 17:380–383
77. Umansky V, Abschuetz O, Osen W, Ramacher M, Zhao F, Kato M, Schadendorf D (2008) Melanoma-specific memory T cells are functionally active in ret transgenic mice without macroscopic tumors. Cancer Res 68:9451–9458
78. Livingstone E, Zimmer L, Vaubel J, Schadendorf D (2012) Current advances and perspectives in the treatment of advanced melanoma. J Dtsch Dermatol Ges 10:319–325
79. Abschuetz O, Osen W, Frank K, Kato M, Schadendorf D, Umansky V (2012) T-cell mediated immune responses induced in ret transgenic mouse model of malignant melanoma. Cancers (Basel) 4:490–503
80. Zhao F, Falk C, Osen W, Kato M, Schadendorf D, Umansky V (2009) Activation of p38 mitogen-activated protein kinase drives dendritic cells to become tolerogenic in ret transgenic mice spontaneously developing melanoma. Clin Cancer Res 15:4382–4390
81. Lugowska I, Kowalska M, Fuksiewicz M, Kotowicz B, Mierzejewska E, Koseła-Paterczyk H, Szamotulska K, Rutkowski P (2015) Serum markers in early-stage and locally advanced melanoma. Tumour Biol 36:8277–8285
82. Rider P, Carmi Y, Voronov E, Apte RN (2013) Interleukin-1α. Semin Immunol 25:430–438
83. Bonecchi R, Locati M, Mantovani A (2011) Chemokines and cancer: a fatal attraction. Cancer Cell 19:434–435
84. Kimpfler S, Sevko A, Ring S, Falk C, Osen W, Frank K, Kato M, Mahnke K, Schadendorf D, Umansky V (2009) Skin melanoma development in ret transgenic mice despite the depletion of CD25 + Foxp3+ regulatory T cells in lymphoid organs. J Immunol 183:6330–6337
85. 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 136:2352–2360
86. 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 62:1711–1722
87. 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 20:1601–1609
88. 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 1:158–162
89. 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:e57114
90. 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 118:2254–2265
91. Tkach M, Thery C (2016) Communication by extracellular vesicles: where we are and where we need to go. Cell 164:1226–1232
92. Hendrix A, Westbroek W, Bracke M, Wever OD (2010) An ex(o)citing machinery for invasive tumor growth. Cancer Res 70:9533–9537
93. Raiborg C, Rusten TE, Stenmark H (2003) Protein sorting into multivesicular endosomes. Current Opin Cell Biol 15:446–455
94. Ginestra A, La Placa MD, Saladino F, Cassara D, Nagase H, Vittorelli ML (1998) The amount and proteolytic content of vesicles shed by human cancer cell lines correlates with their in vitro invasiveness. Anticancer Res 18(5A):3433–3437
95. Camussi G, Deregibus MC, Bruno S, Cantaluppi V, Biancone L (2010) Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int 78:838–848
96. Bretz NP, Ridinger J, Rupp AK, Rimbach K, Keller S, Rupp C, Marme F, Umansky L, Umansky V, Eigenbrod T, Sammar M, Altevogt P (2013) Body fluid exosomes promote secretion of inflammatory cytokines in monocytic cells via toll-like receptor signaling. J Biol Chem 288:36691–36702
97. Chow A, Zhou W, Liu L, Fong MY, Champer J, Van Haute D, Chin AR, Ren X, Gugiu BG, Meng Z, Huang W, Ngo V, Kortylewski M, Wang SE (2014) Macrophage immunomodulation by breast cancer-derived exosomes requires toll-like receptor 2-mediated activation of NF-kappaB. Sci Rep 4:5750
98. Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin JP, Boireau W, Rouleau A, Simon B, Lanneau D, De Thonel A, Multhoff G, Hamman A, Martin F, Chauffert B, Solary E, Zitvogel L, Garrido C, Ryffel B, Borg C, Apetoh L, Rébé C, Ghiringhelli F (2010) Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest 120:457–471
99. Altevogt P, Bretz NP, Ridinger J, Utikal J, Umansky V (2014) Novel insights into exosome-induced, tumor-associated inflammation and immunomodulation. Semin Cancer Biol 28:51–57
100. Gajos-Michniewicz A, Duechler M, Czyz M (2014) MiRNA in melanoma-derived exosomes. Cancer Lett 347:29–37
101. Felicetti F, De Feo A, Coscia C, Puglisi R, Pedini F, Pasquini L, Bellenghi M, Errico MC, Pagani E, Care A (2016) Exosome-mediated transfer of miR-222 is sufficient to increase tumor malignancy in melanoma. J Transl Med 14:56
102. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar C, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan J, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang Y, Bromberg J, Lyden D (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18:883–891
103. Ridder K, Sevko A, Heide J, Dams M, Rupp AK, Macas J, Starmann J, Tjwa M, Plate KH, Sultmann H, Altevogt P, Umansky V, Momma S (2015) Extracellular vesicle-mediated transfer of functional RNA in the tumor microenvironment. Oncoimmunology 4:e1008371
104. Liu Y, Gu Y, Han Y, Zhang Q, Jiang Z, Zhang X, Huang B, Xu X, Zheng J, Cao X (2016) Tumor exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils. Cancer Cell 30:243–256
105. Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, Lovat F, Fadda P, Mao C, Nuovo GJ, Zanesi N, Crawford M, Ozer GH, Wernicke D, Alder H, Caligiuri MA, Nana-Sinkam P, Perrotti D, Croce CM (2012) MicroRNAs bind to toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A 109:E2110–E2116
106. 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 527:329–335
107. Hood JL, San RS, Wickline SA (2011) Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res 71:3792–3801
108. Dror S, Sander L, Schwartz H, Sheinboim D, Barzilai A, Dishon Y, Apcher S, Golan T, Greenberger S, Barshack I, Malcov H, Zilberberg A, Levin L, Nessling M, Friedmann Y, Igras V, Barzilay O, Vaknine H, Brenner R, Zinger A, Schroeder A, Gonen P, Khaled M, Erez N, Hoheisel JD, Levy C (2016) Melanoma miRNA trafficking controls tumour primary niche formation. Nat Cell Biol 18:1006–1017
109. Andreola G, Rivoltini L, Castelli C, Huber V, Perego P, Deho P, Squarcina P, Accornero P, Lozupone F, Lugini L, Stringaro A, Molinari A, Arancia G, Gentile M, Parmiani G, Fais S (2002) Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J Exp Med 195:1303–1316