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Molecular mechanisms involved in dendritic cell dysfunction in cancer

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Abstract

Dendritic cells (DC) play a pivotal role in the tumor microenvironment (TME). As the primary antigen-presenting cells in the tumor, DCs modulate anti-tumor responses by regulating the magnitude and duration of infiltrating cytotoxic T lymphocyte responses. Unfortunately, due to the immunosuppressive nature of the TME, as well as the inherent plasticity of DCs, tumor DCs are often dysfunctional, a phenomenon that contributes to immune evasion. Recent progresses in our understanding of tumor DC biology have revealed potential molecular targets that allow us to improve tumor DC immunogenicity and cancer immunotherapy. Here, we review the molecular mechanisms that drive tumor DC dysfunction. We discuss recent advances in our understanding of tumor DC ontogeny, tumor DC subset heterogeneity, and factors in the tumor microenvironment that affect DC recruitment, differentiation, and function. Finally, we describe potential strategies to optimize tumor DC function in the context of cancer therapy.

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Abbreviations

CDPs:

Common DC precursors

cMoP:

Common monocyte progenitors

CTLs:

Cytotoxic T lymphocytes

DAMP:

Danger-associated molecular patterns

DCs:

Dendritic cells

ER:

Endoplasmic reticulum

FABP4:

Fatty acid-binding protein 4

Flt3L:

FMS-like tyrosine kinase 3 ligand

GM-CSF:

Granulocyte/macrophage colony-stimulating factor

HMGB1:

High mobility group box 1

ICD:

Immunogenic cell death

IDO:

Indoleamine 2,3-dioxygenase

IL-10R:

Interleukin-10 receptor

LC:

Langerhans cells

LPL:

Lipoprotein lipase

MDP:

Monocyte/macrophage and DC progenitor

MDSC:

Myeloid-derived suppressor cells

MHC:

Major histocompatibility complex

NO:

Nitric oxide

pDC:

Plasmacytoid dendritic cells

STAT3:

Signal transducer and activator of transcription 3

TAG:

Triacylglycerols

TAMs:

Tumor-associated macrophages

TF:

Transcription factor

TIM-3:

T-cell immunoglobulin and mucin-domain containing-3

TLR:

Toll-like receptor

TME:

Tumor microenvironment

Tregs:

Regulatory T cells

UPR:

Unfolded protein response

VEGF:

Vascular endothelial growth factor

References

  1. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME (2008) Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 8:299–308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252

    Article  CAS  PubMed  Google Scholar 

  3. Steinman RM, Banchereau J (2007) Taking dendritic cells into medicine. Nature 449:419–426

    Article  CAS  PubMed  Google Scholar 

  4. Rabinovich GA, Gabrilovich D, Sotomayor EM (2007) Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, Rivera M, Ravetch JV, Steinman RM, Nussenzweig MC (2001) Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 194:769–779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Steinman RM, Hawiger D, Nussenzweig MC (2003) Tolerogenic dendritic cells. Annu Rev Immunol 21:685–711

    Article  CAS  PubMed  Google Scholar 

  7. Reis ESC (2006) Dendritic cells in a mature age. Nat Rev Immunol 6:476–483

    Article  CAS  Google Scholar 

  8. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801

    Article  CAS  PubMed  Google Scholar 

  9. Jung S, Unutmaz D, Wong P, Sano G, De los Santos K, Sparwasser T, Wu S, Vuthoori S, Ko K, Zavala F, Pamer EG, Littman DR, Lang RA (2002) In vivo depletion of CD11c(+) dendritic cells abrogates priming of CD8(+) T cells by exogenous cell-associated antigens. Immunity 17:211–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zammit DJ, Cauley LS, Pham QM, Lefrancois L (2005) Dendritic cells maximize the memory CD8 T cell response to infection. Immunity 22:561–570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen M, Wang YH, Wang Y, Huang L, Sandoval H, Liu YJ, Wang J (2006) Dendritic cell apoptosis in the maintenance of immune tolerance. Science 311:1160–1164

    Article  CAS  PubMed  Google Scholar 

  12. Chen M, Wang J (2010) Programmed cell death of dendritic cells in immune regulation. Immunol Rev 236:11–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI (2001) Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 166:678–689

    Article  CAS  PubMed  Google Scholar 

  14. Almand B, Resser JR, Lindman B, Nadaf S, Clark JI, Kwon ED, Carbone DP, Gabrilovich DI (2000) Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 6:1755–1766

    CAS  PubMed  Google Scholar 

  15. Vicari AP, Treilleux I, Lebecque S (2004) Regulation of the trafficking of tumour-infiltrating dendritic cells by chemokines. Semin Cancer Biol 14:161–169

    Article  CAS  PubMed  Google Scholar 

  16. Hoffmann TK, Muller-Berghaus J, Ferris RL, Johnson JT, Storkus WJ, Whiteside TL (2002) Alterations in the frequency of dendritic cell subsets in the peripheral circulation of patients with squamous cell carcinomas of the head and neck. Clin Cancer Res 8:1787–1793

    PubMed  Google Scholar 

  17. Della Bella S, Gennaro M, Vaccari M, Ferraris C, Nicola S, Riva A, Clerici M, Greco M, Villa ML (2003) Altered maturation of peripheral blood dendritic cells in patients with breast cancer. Br J Cancer 89:1463–1472

    Article  CAS  PubMed  Google Scholar 

  18. Vicari AP, Caux C, Trinchieri G (2002) Tumour escape from immune surveillance through dendritic cell inactivation. Semin Cancer Biol 12:33–42

    Article  CAS  PubMed  Google Scholar 

  19. 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 16:880–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Merad M, Sathe P, Helft J, Miller J, Mortha A (2013) The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol 31:563–604

    Article  CAS  PubMed  Google Scholar 

  21. 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 14:571–578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ginhoux F, Jung S (2014) Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 14:392–404

    Article  CAS  PubMed  Google Scholar 

  23. Diao J, Winter E, Chen W, Cantin C, Cattral MS (2004) Characterization of distinct conventional and plasmacytoid dendritic cell-committed precursors in murine bone marrow. J Immunol 173:1826–1833

    Article  CAS  PubMed  Google Scholar 

  24. Diao J, Winter E, Cantin C, Chen W, Xu L, Kelvin D, Phillips J, Cattral MS (2006) In situ replication of immediate dendritic cell (DC) precursors contributes to conventional dc homeostasis in lymphoid tissue. J Immunol 176:7196–7206

    Article  CAS  PubMed  Google Scholar 

  25. Naik SH, Metcalf D, van Nieuwenhuijze A, Wicks I, Wu L, O’Keeffe M, Shortman K (2006) Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nat Immunol 7:663–671

    Article  CAS  PubMed  Google Scholar 

  26. Naik SH, Sathe P, Park H-Y, Metcalf D, Proietto AI, Dakic A, Carotta S, O’Keeffe M, Bahlo M, Papenfuss A, Kwak J-Y, Wu L, Shortman K (2007) Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo. Nat Immunol 8:1217–1226

    Article  CAS  PubMed  Google Scholar 

  27. Onai N, Obata-Onai A, Schmid MA, Ohteki T, Jarrossay D, Manz MG (2007) Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow. Nat Immunol 8:1207–1216

    Article  CAS  PubMed  Google Scholar 

  28. Liu K, Victora GD, Schwickert TA, Guermonprez P, Meredith MM, Yao K, Chu FF, Randolph GJ, Rudensky AY, Nussenzweig M (2009) In vivo analysis of dendritic cell development and homeostasis. Science 324:392–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Satpathy AT, Kc W, Albring JC, Edelson BT, Kretzer NM, Bhattacharya D, Murphy TL, Murphy KM (2012) Zbtb46 expression distinguishes classical dendritic cells and their committed progenitors from other immune lineages. J Exp Med 209:1135–1152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Meredith MM, Liu K, Darrasse-Jeze G, Kamphorst AO, Schreiber HA, Guermonprez P, Idoyaga J, Cheong C, Yao KH, Niec RE, Nussenzweig MC (2012) Expression of the zinc finger transcription factor zDC (Zbtb46, Btbd4) defines the classical dendritic cell lineage. J Exp Med 209:1153–1165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Schlitzer A, Sivakamasundari V, Chen J, Sumatoh HR, Schreuder J, Lum J, Malleret B, Zhang S, Larbi A, Zolezzi F, Renia L, Poidinger M, Naik S, Newell EW, Robson P, Ginhoux F (2015) Identification of cDC1- and cDC2-committed DC progenitors reveals early lineage priming at the common DC progenitor stage in the bone marrow. Nat Immunol 16:718–728

    Article  CAS  PubMed  Google Scholar 

  32. Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, Kohyama M, Calderon B, Schraml BU, Unanue ER, Diamond MS, Schreiber RD, Murphy TL, Murphy KM (2008) Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 322:1097–1100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Suzuki S, Honma K, Matsuyama T, Suzuki K, Toriyama K, Akitoyo I, Yamamoto K, Suematsu T, Nakamura M, Yui K, Kumatori A (2004) Critical roles of interferon regulatory factor 4 in CD11bhighCD8alpha− dendritic cell development. Proc Natl Acad Sci USA 101:8981–8986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ginhoux F, Liu K, Helft J, Bogunovic M, Greter M, Hashimoto D, Price J, Yin N, Bromberg J, Lira SA, Stanley ER, Nussenzweig M, Merad M (2009) The origin and development of nonlymphoid tissue CD103+ DCs. J Exp Med 206:3115–3130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Varol C, Landsman L, Fogg DK, Greenshtein L, Gildor B, Margalit R, Kalchenko V, Geissmann F, Jung S (2007) Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J Exp Med 204:171–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bogunovic M, Ginhoux F, Helft J, Shang L, Hashimoto D, Greter M, Liu K, Jakubzick C, Ingersoll MA, Leboeuf M, Stanley ER, Nussenzweig M, Lira SA, Randolph GJ, Merad M (2009) Origin of the lamina propria dendritic cell network. Immunity 31:513–525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Karsunky H, Merad M, Cozzio A, Weissman IL, Manz MG (2003) Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid-committed progenitors to Flt3+ dendritic cells in vivo. J Exp Med 198:305–313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Liu K, Nussenzweig MC (2010) Origin and development of dendritic cells. Immunol Rev 234:45–54

    Article  CAS  PubMed  Google Scholar 

  39. Waskow C, Liu K, Darrasse-Jeze G, Guermonprez P, Ginhoux F, Merad M, Shengelia T, Yao K, Nussenzweig M (2008) The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues. Nat Immunol 9:676–683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Maraskovsky E, Daro E, Roux E, Teepe M, Maliszewski CR, Hoek J, Caron D, Lebsack ME, McKenna HJ (2000) In vivo generation of human dendritic cell subsets by Flt3 ligand. Blood 96:878–884

    CAS  PubMed  Google Scholar 

  41. Manfra DJ, Chen SC, Jensen KK, Fine JS, Wiekowski MT, Lira SA (2003) Conditional expression of murine Flt3 ligand leads to expansion of multiple dendritic cell subsets in peripheral blood and tissues of transgenic mice. J Immunol 170:2843–2852

    Article  CAS  PubMed  Google Scholar 

  42. Kingston D, Schmid MA, Onai N, Obata-Onai A, Baumjohann D, Manz MG (2009) The concerted action of GM-CSF and Flt3-ligand on in vivo dendritic cell homeostasis. Blood 114:835–843

    Article  CAS  PubMed  Google Scholar 

  43. Kabashima K, Banks TA, Ansel KM, Lu TT, Ware CF, Cyster JG (2005) Intrinsic lymphotoxin-beta receptor requirement for homeostasis of lymphoid tissue dendritic cells. Immunity 22:439–450

    Article  CAS  PubMed  Google Scholar 

  44. Lewis KL, Caton ML, Bogunovic M, Greter M, Grajkowska LT, Ng D, Klinakis A, Charo IF, Jung S, Gommerman JL, Ivanov II, Liu K, Merad M, Reizis B (2011) Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35:780–791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Klebanoff CA, Spencer SP, Torabi-Parizi P, Grainger JR, Roychoudhuri R, Ji Y, Sukumar M, Muranski P, Scott CD, Hall JA, Ferreyra GA, Leonardi AJ, Borman ZA, Wang J, Palmer DC, Wilhelm C, Cai R, Sun J, Napoli JL, Danner RL, Gattinoni L, Belkaid Y, Restifo NP (2013) Retinoic acid controls the homeostasis of pre-cDC-derived splenic and intestinal dendritic cells. J Exp Med 210:1961–1976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Diao J, Winter E, Chen W, Xu F, Cattral MS (2007) Antigen transmission by replicating antigen-bearing dendritic cells. J Immunol 179:2713–2721

    Article  CAS  PubMed  Google Scholar 

  47. Sponaas AM, Cadman ET, Voisine C, Harrison V, Boonstra A, O’Garra A, Langhorne J (2006) Malaria infection changes the ability of splenic dendritic cell populations to stimulate antigen-specific T cells. J Exp Med 203:1427–1433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nakano H, Lin KL, Yanagita M, Charbonneau C, Cook DN, Kakiuchi T, Gunn MD (2009) Blood-derived inflammatory dendritic cells in lymph nodes stimulate acute T helper type 1 immune responses. Nat Immunol 10:394–402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Cheong C, Matos I, Choi JH, Dandamudi DB, Shrestha E, Longhi MP, Jeffrey KL, Anthony RM, Kluger C, Nchinda G, Koh H, Rodriguez A, Idoyaga J, Pack M, Velinzon K, Park CG, Steinman RM (2010) Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209(+) dendritic cells for immune T cell areas. Cell 143:416–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Metcalf D, Nicola NA, Mifsud S, Di Rago L (1999) Receptor clearance obscures the magnitude of granulocyte-macrophage colony-stimulating factor responses in mice to endotoxin or local infections. Blood 93:1579–1585

    CAS  PubMed  Google Scholar 

  51. Greter M, Helft J, Chow A, Hashimoto D, Mortha A, Agudo-Cantero J, Bogunovic M, Gautier EL, Miller J, Leboeuf M, Lu G, Aloman C, Brown BD, Pollard JW, Xiong H, Randolph GJ, Chipuk JE, Frenette PS, Merad M (2012) GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells. Immunity 36:1031–1046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. MacPherson GG, Jenkins CD, Stein MJ, Edwards C (1995) Endotoxin-mediated dendritic cell release from the intestine. Characterization of released dendritic cells and TNF dependence. J Immunol 154:1317–1322

    CAS  PubMed  Google Scholar 

  53. Jakubzick C, Bogunovic M, Bonito AJ, Kuan EL, Merad M, Randolph GJ (2008) Lymph-migrating, tissue-derived dendritic cells are minor constituents within steady-state lymph nodes. J Exp Med 205:2839–2850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Angeli V, Ginhoux F, Llodra J, Quemeneur L, Frenette PS, Skobe M, Jessberger R, Merad M, Randolph GJ (2006) B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 24:203–215

    Article  CAS  PubMed  Google Scholar 

  55. Miller JC, Brown BD, Shay T, Gautier EL, Jojic V, Cohain A, Pandey G, Leboeuf M, Elpek KG, Helft J, Hashimoto D, Chow A, Price J, Greter M, Bogunovic M, Bellemare-Pelletier A, Frenette PS, Randolph GJ, Turley SJ, Merad M (2012) Deciphering the transcriptional network of the dendritic cell lineage. Nat Immunol 13:888–899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Cisse B, Caton ML, Lehner M, Maeda T, Scheu S, Locksley R, Holmberg D, Zweier C, den Hollander NS, Kant SG, Holter W, Rauch A, Zhuang Y, Reizis B (2008) Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell 135:37–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ghosh HS, Cisse B, Bunin A, Lewis KL, Reizis B (2010) Continuous expression of the transcription factor e2-2 maintains the cell fate of mature plasmacytoid dendritic cells. Immunity 33:905–916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hacker C, Kirsch RD, Ju XS, Hieronymus T, Gust TC, Kuhl C, Jorgas T, Kurz SM, Rose-John S, Yokota Y, Zenke M (2003) Transcriptional profiling identifies Id2 function in dendritic cell development. Nat Immunol 4:380–386

    Article  CAS  PubMed  Google Scholar 

  59. Tamura T, Tailor P, Yamaoka K, Kong HJ, Tsujimura H, O’Shea JJ, Singh H, Ozato K (2005) IFN regulatory factor-4 and -8 govern dendritic cell subset development and their functional diversity. J Immunol 174:2573–2581

    Article  CAS  PubMed  Google Scholar 

  60. Kashiwada M, Pham NL, Pewe LL, Harty JT, Rothman PB (2011) NFIL3/E4BP4 is a key transcription factor for CD8alpha(+) dendritic cell development. Blood 117:6193–6197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wu L, D’Amico A, Winkel KD, Suter M, Lo D, Shortman K (1998) RelB is essential for the development of myeloid-related CD8alpha− dendritic cells but not of lymphoid-related CD8alpha+ dendritic cells. Immunity 9:839–847

    Article  CAS  PubMed  Google Scholar 

  62. Hambleton S, Salem S, Bustamante J, Bigley V, Boisson-Dupuis S, Azevedo J, Fortin A, Haniffa M, Ceron-Gutierrez L, Bacon CM, Menon G, Trouillet C, McDonald D, Carey P, Ginhoux F, Alsina L, Zumwalt TJ, Kong XF, Kumararatne D, Butler K, Hubeau M, Feinberg J, Al-Muhsen S, Cant A, Abel L, Chaussabel D, Doffinger R, Talesnik E, Grumach A, Duarte A, Abarca K, Moraes-Vasconcelos D, Burk D, Berghuis A, Geissmann F, Collin M, Casanova JL, Gros P (2011) IRF8 mutations and human dendritic-cell immunodeficiency. N Engl J Med 365:127–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Dickinson RE, Griffin H, Bigley V, Reynard LN, Hussain R, Haniffa M, Lakey JH, Rahman T, Wang XN, McGovern N, Pagan S, Cookson S, McDonald D, Chua I, Wallis J, Cant A, Wright M, Keavney B, Chinnery PF, Loughlin J, Hambleton S, Santibanez-Koref M, Collin M (2011) Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood 118:2656–2658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Restifo NP, Dudley ME, Rosenberg SA (2012) Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol 12:269–281

    Article  CAS  PubMed  Google Scholar 

  66. Vormehr M, Diken M, Boegel S, Kreiter S, Tureci O, Sahin U (2016) Mutanome directed cancer immunotherapy. Curr Opin Immunol 39:14–22

    Article  CAS  PubMed  Google Scholar 

  67. Finn OJ (2008) Cancer immunology. N Engl J Med 358:2704–2715

    Article  CAS  PubMed  Google Scholar 

  68. MacKie RM, Reid R, Junor B (2003) Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery. N Engl J Med 348:567–568

    Article  PubMed  Google Scholar 

  69. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964

    Article  CAS  PubMed  Google Scholar 

  70. Budhu S, Loike JD, Pandolfi A, Han S, Catalano G, Constantinescu A, Clynes R, Silverstein SC (2010) CD8 + T cell concentration determines their efficiency in killing cognate antigen-expressing syngeneic mammalian cells in vitro and in mouse tissues. J Exp Med 207:223–235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22:329–360

    Article  CAS  PubMed  Google Scholar 

  72. DuPage M, Mazumdar C, Schmidt LM, Cheung AF, Jacks T (2012) Expression of tumour-specific antigens underlies cancer immunoediting. Nature 482:405–409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Sica A, Bronte V (2007) Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 117:1155–1166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Beyer M, Schultze JL (2006) Regulatory T cells in cancer. Blood 108:804–811

    Article  CAS  PubMed  Google Scholar 

  75. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT (2010) Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330:827–830

    Article  CAS  PubMed  Google Scholar 

  76. Yao X, Ahmadzadeh M, Lu YC, Liewehr DJ, Dudley ME, Liu F, Schrump DS, Steinberg SM, Rosenberg SA, Robbins PF (2012) Levels of peripheral CD4(+)FoxP3(+) regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood 119:5688–5696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bennett CL, Chakraverty R (2012) Dendritic cells in tissues: in situ stimulation of immunity and immunopathology. Trends Immunol 33:8–13

    Article  CAS  PubMed  Google Scholar 

  78. Wakim LM, Waithman J, van Rooijen N, Heath WR, Carbone FR (2008) Dendritic cell-induced memory T cell activation in nonlymphoid tissues. Science 319:198–202

    Article  CAS  PubMed  Google Scholar 

  79. McGill J, Van Rooijen N, Legge KL (2008) Protective influenza-specific CD8 T cell responses require interactions with dendritic cells in the lungs. J Exp Med 205:1635–1646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. McGill J, Van Rooijen N, Legge KL (2010) IL-15 trans-presentation by pulmonary dendritic cells promotes effector CD8 T cell survival during influenza virus infection. J Exp Med 207:521–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mrass P, Takano H, Ng LG, Daxini S, Lasaro MO, Iparraguirre A, Cavanagh LL, von Andrian UH, Ertl HC, Haydon PG, Weninger W (2006) Random migration precedes stable target cell interactions of tumor-infiltrating T cells. J Exp Med 203:2749–2761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Engelhardt JJ, Boldajipour B, Beemiller P, Pandurangi P, Sorensen C, Werb Z, Egeblad M, Krummel MF (2012) Marginating dendritic cells of the tumor microenvironment cross-present tumor antigens and stably engage tumor-specific T cells. Cancer Cell 21:402–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Diao J, Zhao J, Winter E, Cattral MS (2011) Tumors suppress in situ proliferation of cytotoxic T cells by promoting differentiation of Gr-1(+) conventional dendritic cells through IL-6. J Immunol 186:5058–5067

    Article  CAS  PubMed  Google Scholar 

  84. 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 26:638–652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Broz ML, Krummel MF (2015) The emerging understanding of myeloid cells as partners and targets in tumor rejection. Cancer Immunol Res 3:313–319

    Article  PubMed  PubMed Central  Google Scholar 

  86. Karthaus N, Torensma R, Tel J (2012) Deciphering the message broadcast by tumor-infiltrating dendritic cells. Am J Pathol 181:733–742

    Article  CAS  PubMed  Google Scholar 

  87. Diao J, Zhao J, Winter E, Cattral MS (2010) Recruitment and differentiation of conventional dendritic cell precursors in tumors. J Immunol 184:1261–1267

    Article  CAS  PubMed  Google Scholar 

  88. Salmon H, Idoyaga J, Rahman A, Leboeuf M, Remark R, Jordan S, Casanova-Acebes M, Khudoynazarova M, Agudo J, Tung N, Chakarov S, Rivera C, Hogstad B, Bosenberg M, Hashimoto D, Gnjatic S, Bhardwaj N, Palucka AK, Brown BD, Brody J, Ginhoux F, Merad M (2016) Expansion and activation of CD103(+) dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 44:924–938

    Article  CAS  PubMed  Google Scholar 

  89. Ma Y, Adjemian S, Mattarollo SR, Yamazaki T, Aymeric L, Yang H, Portela Catani JP, Hannani D, Duret H, Steegh K, Martins I, Schlemmer F, Michaud M, Kepp O, Sukkurwala AQ, Menger L, Vacchelli E, Droin N, Galluzzi L, Krzysiek R, Gordon S, Taylor PR, Van Endert P, Solary E, Smyth MJ, Zitvogel L, Kroemer G (2013) Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38:729–741

    Article  CAS  PubMed  Google Scholar 

  90. Ma Y, Mattarollo SR, Adjemian S, Yang H, Aymeric L, Hannani D, Portela Catani JP, Duret H, Teng MW, Kepp O, Wang Y, Sistigu A, Schultze JL, Stoll G, Galluzzi L, Zitvogel L, Smyth MJ, Kroemer G (2014) CCL2/CCR2-dependent recruitment of functional antigen-presenting cells into tumors upon chemotherapy. Cancer Res 74:436–445

    Article  CAS  PubMed  Google Scholar 

  91. Scarlett UK, Rutkowski MR, Rauwerdink AM, Fields J, Escovar-Fadul X, Baird J, Cubillos-Ruiz JR, Jacobs AC, Gonzalez JL, Weaver J, Fiering S, Conejo-Garcia JR (2012) Ovarian cancer progression is controlled by phenotypic changes in dendritic cells. J Exp Med 209:495–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Krempski J, Karyampudi L, Behrens MD, Erskine CL, Hartmann L, Dong H, Goode EL, Kalli KR, Knutson KL (2011) Tumor-infiltrating programmed death receptor-1+ dendritic cells mediate immune suppression in ovarian cancer. J Immunol 186:6905–6913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Diao J, Mikhailova A, Tang M, Gu H, Zhao J, Cattral MS (2012) Immunostimulatory conventional dendritic cells evolve into regulatory macrophage-like cells. Blood 119:4919–4927

    Article  CAS  PubMed  Google Scholar 

  94. Lin ML, Zhan Y, Villadangos JA, Lew AM (2008) The cell biology of cross-presentation and the role of dendritic cell subsets. Immunol Cell Biol 86:353–362

    Article  CAS  PubMed  Google Scholar 

  95. van der Bruggen P, Van den Eynde BJ (2006) Processing and presentation of tumor antigens and vaccination strategies. Curr Opin Immunol 18:98–104

    Article  PubMed  CAS  Google Scholar 

  96. Berg M, Wingender G, Djandji D, Hegenbarth S, Momburg F, Hammerling G, Limmer A, Knolle P (2006) Cross-presentation of antigens from apoptotic tumor cells by liver sinusoidal endothelial cells leads to tumor-specific CD8+ T cell tolerance. Eur J Immunol 36:2960–2970

    Article  CAS  PubMed  Google Scholar 

  97. Blachere NE, Darnell RB, Albert ML (2005) Apoptotic cells deliver processed antigen to dendritic cells for cross-presentation. PLoS Biol 3:e185

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Fonseca C, Dranoff G (2008) Capitalizing on the immunogenicity of dying tumor cells. Clin Cancer Res 14:1603–1608

    Article  CAS  PubMed  Google Scholar 

  99. Binder RJ, Kelly JB 3rd, Vatner RE, Srivastava PK (2007) Specific immunogenicity of heat shock protein gp96 derives from chaperoned antigenic peptides and not from contaminating proteins. J Immunol 179:7254–7261

    Article  CAS  PubMed  Google Scholar 

  100. Giodini A, Cresswell P (2008) Hsp90-mediated cytosolic refolding of exogenous proteins internalized by dendritic cells. EMBO J 27:201–211

    Article  CAS  PubMed  Google Scholar 

  101. Zeelenberg IS, Ostrowski M, Krumeich S, Bobrie A, Jancic C, Boissonnas A, Delcayre A, Le Pecq JB, Combadiere B, Amigorena S, Thery C (2008) Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses. Cancer Res 68:1228–1235

    Article  CAS  PubMed  Google Scholar 

  102. Neijssen J, Herberts C, Drijfhout JW, Reits E, Janssen L, Neefjes J (2005) Cross-presentation by intercellular peptide transfer through gap junctions. Nature 434:83–88

    Article  CAS  PubMed  Google Scholar 

  103. Harshyne LA, Watkins SC, Gambotto A, Barratt-Boyes SM (2001) Dendritic cells acquire antigens from live cells for cross-presentation to CTL. J Immunol 166:3717–3723

    Article  CAS  PubMed  Google Scholar 

  104. Dolan BP, Gibbs KD Jr, Ostrand-Rosenberg S (2006) Dendritic cells cross-dressed with peptide MHC class I complexes prime CD8+ T cells. J Immunol 177:6018–6024

    Article  CAS  PubMed  Google Scholar 

  105. Dolan BP, Gibbs KD Jr, Ostrand-Rosenberg S (2006) Tumor-specific CD4+ T cells are activated by “cross-dressed” dendritic cells presenting peptide-MHC class II complexes acquired from cell-based cancer vaccines. J Immunol 176:1447–1455

    Article  CAS  PubMed  Google Scholar 

  106. Melief CJ (2008) Cancer immunotherapy by dendritic cells. Immunity 29:372–383

    Article  CAS  PubMed  Google Scholar 

  107. van Mierlo GJ, Boonman ZF, Dumortier HM, den Boer AT, Fransen MF, Nouta J, van der Voort EI, Offringa R, Toes RE, Melief CJ (2004) Activation of dendritic cells that cross-present tumor-derived antigen licenses CD8+ CTL to cause tumor eradication. J Immunol 173:6753–6759

    Article  PubMed  Google Scholar 

  108. Gerner MY, Casey KA, Mescher MF (2008) Defective MHC class II presentation by dendritic cells limits CD4 T cell help for antitumor CD8 T cell responses. J Immunol 181:155–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. McDonnell AM, Prosser AC, van Bruggen I, Robinson BW, Currie AJ (2010) CD8alpha+ DC are not the sole subset cross-presenting cell-associated tumor antigens from a solid tumor. Eur J Immunol 40:1617–1627

    Article  CAS  PubMed  Google Scholar 

  110. Stoitzner P, Green LK, Jung JY, Price KM, Atarea H, Kivell B, Ronchese F (2008) Inefficient presentation of tumor-derived antigen by tumor-infiltrating dendritic cells. Cancer Immunol Immunother 57:1665–1673

    Article  CAS  PubMed  Google Scholar 

  111. Headley MB, Bins A, Nip A, Roberts EW, Looney MR, Gerard A, Krummel MF (2016) Visualization of immediate immune responses to pioneer metastatic cells in the lung. Nature 531:513–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 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 26:623–637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Savina A, Jancic C, Hugues S, Guermonprez P, Vargas P, Moura IC, Lennon-Dumenil AM, Seabra MC, Raposo G, Amigorena S (2006) NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. Cell 126:205–218

    Article  CAS  PubMed  Google Scholar 

  114. Spranger S, Bao R, Gajewski TF (2015) Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523:231–235

    Article  CAS  PubMed  Google Scholar 

  115. Segura E, Durand M, Amigorena S (2013) Similar antigen cross-presentation capacity and phagocytic functions in all freshly isolated human lymphoid organ-resident dendritic cells. J Exp Med 210:1035–1047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Desch AN, Gibbings SL, Clambey ET, Janssen WJ, Slansky JE, Kedl RM, Henson PM, Jakubzick C (2014) Dendritic cell subsets require cis-activation for cytotoxic CD8 T-cell induction. Nat Commun 5:4674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Melief CJ (2003) Mini-review: regulation of cytotoxic T lymphocyte responses by dendritic cells: peaceful coexistence of cross-priming and direct priming? Eur J Immunol 33:2645–2654

    Article  CAS  PubMed  Google Scholar 

  118. Steinman RM, Nussenzweig MC (2002) Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci USA 99:351–358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Tran Janco JM, Lamichhane P, Karyampudi L, Knutson KL (2015) Tumor-infiltrating dendritic cells in cancer pathogenesis. J Immunol 194:2985–2991

    Article  PubMed  CAS  Google Scholar 

  120. Karyampudi L, Lamichhane P, Scheid AD, Kalli KR, Shreeder B, Krempski JW, Behrens MD, Knutson KL (2014) Accumulation of memory precursor CD8 T cells in regressing tumors following combination therapy with vaccine and anti-PD-1 antibody. Cancer Res 74:2974–2985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Karyampudi L, Lamichhane P, Krempski J, Kalli KR, Behrens MD, Vargas DM, Hartmann LC, Janco JM, Dong H, Hedin KE, Dietz AB, Goode EL, Knutson KL (2016) PD-1 blunts the function of ovarian tumor-infiltrating dendritic cells by inactivating NF-kappaB. Cancer Res 76:239–250

    Article  CAS  PubMed  Google Scholar 

  122. Munn DH, Bronte V (2016) Immune suppressive mechanisms in the tumor microenvironment. Curr Opin Immunol 39:1–6

    Article  CAS  PubMed  Google Scholar 

  123. Norian LA, Rodriguez PC, O’Mara LA, Zabaleta J, Ochoa AC, Cella M, Allen PM (2009) Tumor-infiltrating regulatory dendritic cells inhibit CD8 + T cell function via l-arginine metabolism. Cancer Res 69:3086–3094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Baban B, Chandler PR, Sharma MD, Pihkala J, Koni PA, Munn DH, Mellor AL (2009) IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol 183:2475–2483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Popov A, Schultze JL (2008) IDO-expressing regulatory dendritic cells in cancer and chronic infection. J Mol Med (Berl) 86:145–160

    Article  CAS  Google Scholar 

  126. Munn DH, Mellor AL (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117:1147–1154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Gabrilovich D (2004) Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 4:941–952

    Article  CAS  PubMed  Google Scholar 

  129. Guilliams M, Malissen B (2015) A death notice for in-vitro-generated GM-CSF dendritic cells? Immunity 42:988–990

    Article  CAS  PubMed  Google Scholar 

  130. Helft J, Bottcher J, Chakravarty P, Zelenay S, Huotari J, Schraml BU, Goubau D, Reis e Sousa C (2015) GM-CSF mouse bone marrow cultures comprise a heterogeneous population of CD11c(+)MHCII(+) macrophages and dendritic cells. Immunity 42:1197–1211

    Article  CAS  PubMed  Google Scholar 

  131. Bell D, Chomarat P, Broyles D, Netto G, Harb GM, Lebecque S, Valladeau J, Davoust J, Palucka KA, Banchereau J (1999) In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med 190:1417–1426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Ishihara K, Hirano T (2002) IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev 13:357–368

    Article  CAS  PubMed  Google Scholar 

  133. Haura EB, Turkson J, Jove R (2005) Mechanisms of disease: insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol 2:315–324

    Article  CAS  PubMed  Google Scholar 

  134. Kim S, Takahashi H, Lin W-W, Descargues P, Grivennikov S, Kim Y, Luo J-L, Karin M (2009) Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457:102–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Lin WW, Karin M (2007) A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 117:1175–1183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Hunter CA, Jones SA (2015) IL-6 as a keystone cytokine in health and disease. Nat Immunol 16:448–457

    Article  CAS  PubMed  Google Scholar 

  137. Mauer J, Chaurasia B, Goldau J, Vogt MC, Ruud J, Nguyen KD, Theurich S, Hausen AC, Schmitz J, Bronneke HS, Estevez E, Allen TL, Mesaros A, Partridge L, Febbraio MA, Chawla A, Wunderlich FT, Bruning JC (2014) Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol 15:423–430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Naugler WE, Karin M (2008) The wolf in sheep’s clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med 14:109–119

    Article  CAS  PubMed  Google Scholar 

  139. Hong DS, Angelo LS, Kurzrock R (2007) Interleukin-6 and its receptor in cancer: implications for translational therapeutics. Cancer 110:1911–1928

    Article  CAS  PubMed  Google Scholar 

  140. Ji J, Shi J, Budhu A, Yu Z, Forgues M, Roessler S, Ambs S, Chen Y, Meltzer PS, Croce CM, Qin LX, Man K, Lo CM, Lee J, Ng IO, Fan J, Tang ZY, Sun HC, Wang XW (2009) MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med 361:1437–1447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ratta M, Fagnoni F, Curti A, Vescovini R, Sansoni P, Oliviero B, Fogli M, Ferri E, Della Cuna GR, Tura S, Baccarani M, Lemoli RM (2002) Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood 100:230–237

    Article  CAS  PubMed  Google Scholar 

  142. Hegde S, Pahne J, Smola-Hess S (2004) Novel immunosuppressive properties of interleukin-6 in dendritic cells: inhibition of NF-kappaB binding activity and CCR7 expression. FASEB J 18:1439–1441

    CAS  PubMed  Google Scholar 

  143. Park SJ, Nakagawa T, Kitamura H, Atsumi T, Kamon H, Sawa S, Kamimura D, Ueda N, Iwakura Y, Ishihara K, Murakami M, Hirano T (2004) IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. J Immunol 173:3844–3854

    Article  CAS  PubMed  Google Scholar 

  144. Kitamura H, Kamon H, Sawa S, Park SJ, Katunuma N, Ishihara K, Murakami M, Hirano T (2005) IL-6-STAT3 controls intracellular MHC class II alphabeta dimer level through cathepsin S activity in dendritic cells. Immunity 23:491–502

    Article  CAS  PubMed  Google Scholar 

  145. Chomarat P, Banchereau J, Davoust J, Palucka AK (2000) IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat Immunol 1:510–514

    Article  CAS  PubMed  Google Scholar 

  146. Bleier JI, Pillarisetty VG, Shah AB, DeMatteo RP (2004) Increased and long-term generation of dendritic cells with reduced function from IL-6-deficient bone marrow. J Immunol 172:7408–7416

    Article  CAS  PubMed  Google Scholar 

  147. Jenkins BJ, Grail D, Inglese M, Quilici C, Bozinovski S, Wong P, Ernst M (2004) Imbalanced gp130-dependent signaling in macrophages alters macrophage colony-stimulating factor responsiveness via regulation of c-fms expression. Mol Cell Biol 24:1453–1463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. O’Garra A, Barrat FJ, Castro AG, Vicari A, Hawrylowicz C (2008) Strategies for use of IL-10 or its antagonists in human disease. Immunol Rev 223:114–131

    Article  PubMed  Google Scholar 

  149. Sredni B, Weil M, Khomenok G, Lebenthal I, Teitz S, Mardor Y, Ram Z, Orenstein A, Kershenovich A, Michowiz S, Cohen YI, Rappaport ZH, Freidkin I, Albeck M, Longo DL, Kalechman Y (2004) Ammonium trichloro(dioxoethylene-o, o′)tellurate (AS101) sensitizes tumors to chemotherapy by inhibiting the tumor interleukin 10 autocrine loop. Cancer Res 64:1843–1852

    Article  CAS  PubMed  Google Scholar 

  150. Yang AS, Lattime EC (2003) Tumor-induced interleukin 10 suppresses the ability of splenic dendritic cells to stimulate CD4 and CD8 T-cell responses. Cancer Res 63:2150–2157

    CAS  PubMed  Google Scholar 

  151. Huang LY, Reis e Sousa C, Itoh Y, Inman J, Scott DE (2001) IL-12 induction by a TH1-inducing adjuvant in vivo: dendritic cell subsets and regulation by IL-10. J Immunol 167:1423–1430

    Article  CAS  PubMed  Google Scholar 

  152. Steinbrink K, Jonuleit H, Muller G, Schuler G, Knop J, Enk AH (1999) Interleukin-10-treated human dendritic cells induce a melanoma-antigen- specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells. Blood 93:1634–1642

    CAS  PubMed  Google Scholar 

  153. Vicari AP, Chiodoni C, Vaure C, Ait-Yahia S, Dercamp C, Matsos F, Reynard O, Taverne C, Merle P, Colombo MP, O’Garra A, Trinchieri G, Caux C (2002) Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med 196:541–549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Kundu N, Fulton AM (1997) Interleukin-10 inhibits tumor metastasis, downregulates MHC class I, and enhances NK lysis. Cell Immunol 180:55–61

    Article  CAS  PubMed  Google Scholar 

  155. Kohno T, Mizukami H, Suzuki M, Saga Y, Takei Y, Shimpo M, Matsushita T, Okada T, Hanazono Y, Kume A, Sato I, Ozawa K (2003) Interleukin-10-mediated inhibition of angiogenesis and tumor growth in mice bearing VEGF-producing ovarian cancer. Cancer Res 63:5091–5094

    CAS  PubMed  Google Scholar 

  156. Vuillefroy de Silly R, Ducimetiere L, Yacoub Maroun C, Dietrich PY, Derouazi M, Walker PR (2015) Phenotypic switch of CD8(+) T cells reactivated under hypoxia toward IL-10 secreting, poorly proliferative effector cells. Eur J Immunol 45:2263–2275

    Article  CAS  PubMed  Google Scholar 

  157. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  CAS  PubMed  Google Scholar 

  158. Toi M, Matsumoto T, Bando H (2001) Vascular endothelial growth factor: its prognostic, predictive, and therapeutic implications. Lancet Oncol 2:667–673

    Article  CAS  PubMed  Google Scholar 

  159. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2:1096–1103

    Article  CAS  PubMed  Google Scholar 

  160. Oyama T, Ran S, Ishida T, Nadaf S, Kerr L, Carbone DP, Gabrilovich DI (1998) Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol 160:1224–1232

    CAS  PubMed  Google Scholar 

  161. Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8:579–591

    Article  CAS  PubMed  Google Scholar 

  162. Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone DP (1998) Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92:4150–4166

    CAS  PubMed  Google Scholar 

  163. Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP (1999) Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res 5:2963–2970

    CAS  PubMed  Google Scholar 

  164. Bowman T, Garcia R, Turkson J, Jove R (2000) STATs in oncogenesis. Oncogene 19:2474–2488

    Article  CAS  PubMed  Google Scholar 

  165. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE Jr (1999) Stat3 as an oncogene. Cell 98:295–303

    Article  CAS  PubMed  Google Scholar 

  166. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D, Heller R, Ellis LM, Karras J, Bromberg J, Pardoll D, Jove R, Yu H (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21:2000–2008

    Article  CAS  PubMed  Google Scholar 

  167. 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 172:464–474

    Article  CAS  PubMed  Google Scholar 

  168. Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D, Dalton W, Jove R, Pardoll D, Yu H (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10:48–54

    Article  PubMed  CAS  Google Scholar 

  169. Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7:41–51

    Article  CAS  PubMed  Google Scholar 

  170. Yu H, Lee H, Herrmann A, Buettner R, Jove R (2014) Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 14:736–746

    Article  CAS  PubMed  Google Scholar 

  171. Braun DA, Fribourg M, Sealfon SC (2013) Cytokine response is determined by duration of receptor and signal transducers and activators of transcription 3 (STAT3) activation. J Biol Chem 288:2986–2993

    Article  CAS  PubMed  Google Scholar 

  172. Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, Aki D, Hanada T, Takeda K, Akira S, Hoshijima M, Hirano T, Chien KR, Yoshimura A (2003) IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol 4:551–556

    Article  CAS  PubMed  Google Scholar 

  173. Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, Niu G, Kay H, Mule J, Kerr WG, Jove R, Pardoll D, Yu H (2005) Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11:1314–1321

    Article  CAS  PubMed  Google Scholar 

  174. Hodge DR, Hurt EM, Farrar WL (2005) The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 41:2502–2512

    Article  CAS  PubMed  Google Scholar 

  175. 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 13:2851–2864

    Article  CAS  PubMed  Google Scholar 

  176. Sanchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA, Manlongat N, Bender O, Kamradt T, Kuchroo VK, Gutierrez-Ramos JC, Coyle AJ, Strom TB (2003) Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol 4:1093–1101

    Article  CAS  PubMed  Google Scholar 

  177. Anderson AC, Anderson DE, Bregoli L, Hastings WD, Kassam N, Lei C, Chandwaskar R, Karman J, Su EW, Hirashima M, Bruce JN, Kane LP, Kuchroo VK, Hafler DA (2007) Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 318:1141–1143

    Article  CAS  PubMed  Google Scholar 

  178. Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, Dosaka-Akita H, Fujioka Y, Ohba Y, Gorman JV, Colgan JD, Hirashima M, Uede T, Takaoka A, Yagita H, Jinushi M (2012) Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol 13:832–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Nagahara K, Arikawa T, Oomizu S, Kontani K, Nobumoto A, Tateno H, Watanabe K, Niki T, Katoh S, Miyake M, Nagahata S, Hirabayashi J, Kuchroo VK, Yamauchi A, Hirashima M (2008) Galectin-9 increases Tim-3+ dendritic cells and CD8+ T cells and enhances antitumor immunity via galectin-9-Tim-3 interactions. J Immunol 181:7660–7669

    Article  CAS  PubMed  Google Scholar 

  180. Maurya N, Gujar R, Gupta M, Yadav V, Verma S, Sen P (2014) Immunoregulation of dendritic cells by the receptor T cell Ig and mucin protein-3 via Bruton’s tyrosine kinase and c-Src. J Immunol 193:3417–3425

    Article  CAS  PubMed  Google Scholar 

  181. Maroof A, English NR, Bedford PA, Gabrilovich DI, Knight SC (2005) Developing dendritic cells become ‘lacy’ cells packed with fat and glycogen. Immunology 115:473–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Gao F, Liu C, Guo J, Sun W, Xian L, Bai D, Liu H, Cheng Y, Li B, Cui J, Zhang C, Cai J (2015) Radiation-driven lipid accumulation and dendritic cell dysfunction in cancer. Sci Rep 5:9613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Cubillos-Ruiz Juan R, Silberman Pedro C, Rutkowski Melanie R, Chopra S, Perales-Puchalt A, Song M, Zhang S, Bettigole Sarah E, Gupta D, Holcomb K, Ellenson Lora H, Caputo T, Lee A-H, Conejo-Garcia Jose R, Glimcher Laurie H (2015) ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 161:1527–1538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Gardner JK, Mamotte CD, Patel P, Yeoh TL, Jackaman C, Nelson DJ (2015) Mesothelioma tumor cells modulate dendritic cell lipid content, phenotype and function. PLoS One 10:e0123563

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. 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 192:2920–2931

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Chen X, Iliopoulos D, Zhang Q, Tang Q, Greenblatt MB, Hatziapostolou M, Lim E, Tam WL, Ni M, Chen Y, Mai J, Shen H, Hu DZ, Adoro S, Hu B, Song M, Tan C, Landis MD, Ferrari M, Shin SJ, Brown M, Chang JC, Liu XS, Glimcher LH (2014) XBP1 promotes triple-negative breast cancer by controlling the HIF1alpha pathway. Nature 508:103–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Hetz C, Chevet E, Harding HP (2013) Targeting the unfolded protein response in disease. Nat Rev Drug Discov 12:703–719

    Article  CAS  PubMed  Google Scholar 

  188. Lee AH, Iwakoshi NN, Anderson KC, Glimcher LH (2003) Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci USA 100:9946–9951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Tang CH, Ranatunga S, Kriss CL, Cubitt CL, Tao J, Pinilla-Ibarz JA, Del Valle JR, Hu CC (2014) Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival. J Clin Invest 124:2585–2598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Iwakoshi NN, Pypaert M, Glimcher LH (2007) The transcription factor XBP-1 is essential for the development and survival of dendritic cells. J Exp Med 204:2267–2275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Osorio F, Tavernier SJ, Hoffmann E, Saeys Y, Martens L, Vetters J, Delrue I, De Rycke R, Parthoens E, Pouliot P, Iwawaki T, Janssens S, Lambrecht BN (2014) The unfolded-protein-response sensor IRE-1alpha regulates the function of CD8alpha + dendritic cells. Nat Immunol 15:248–257

    Article  CAS  PubMed  Google Scholar 

  192. Birkle S, Zeng G, Gao L, Yu RK, Aubry J (2003) Role of tumor-associated gangliosides in cancer progression. Biochimie 85:455–463

    Article  CAS  PubMed  Google Scholar 

  193. Palmano K, Rowan A, Guillermo R, Guan J, McJarrow P (2015) The role of gangliosides in neurodevelopment. Nutrients 7:3891–3913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Peguet-Navarro J, Sportouch M, Popa I, Berthier O, Schmitt D, Portoukalian J (2003) Gangliosides from human melanoma tumors impair dendritic cell differentiation from monocytes and induce their apoptosis. J Immunol 170:3488–3494

    Article  CAS  PubMed  Google Scholar 

  195. Shurin GV, Shurin MR, Bykovskaia S, Shogan J, Lotze MT, Barksdale EM Jr (2001) Neuroblastoma-derived gangliosides inhibit dendritic cell generation and function. Cancer Res 61:363–369

    CAS  PubMed  Google Scholar 

  196. Said N, Sanchez-Carbayo M, Smith SC, Theodorescu D (2012) RhoGDI2 suppresses lung metastasis in mice by reducing tumor versican expression and macrophage infiltration. J Clin Invest 122:1503–1518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Gorter A, Zijlmans HJ, van Gent H, Trimbos JB, Fleuren GJ, Jordanova ES (2010) Versican expression is associated with tumor-infiltrating CD8-positive T cells and infiltration depth in cervical cancer. Mod Pathol 23:1605–1615

    Article  CAS  PubMed  Google Scholar 

  198. Touab M, Villena J, Barranco C, Arumi-Uria M, Bassols A (2002) Versican is differentially expressed in human melanoma and may play a role in tumor development. Am J Pathol 160:549–557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Yang HZ, Cui B, Liu HZ, Mi S, Yan J, Yan HM, Hua F, Lin H, Cai WF, Xie WJ, Lv XX, Wang XX, Xin BM, Zhan QM, Hu ZW (2009) Blocking TLR2 activity attenuates pulmonary metastases of tumor. PLoS One 4:e6520

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. 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, Rebe 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

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Schwabe RF, Jobin C (2013) The microbiome and cancer. Nat Rev Cancer 13:800–812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Kroemer G, Galluzzi L, Kepp O, Zitvogel L (2013) Immunogenic cell death in cancer therapy. Annu Rev Immunol 31:51–72

    Article  CAS  PubMed  Google Scholar 

  203. Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G (2015) Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28:690–714

    Article  CAS  PubMed  Google Scholar 

  204. Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von Torne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28:105–113

    Article  CAS  PubMed  Google Scholar 

  205. Halama N, Michel S, Kloor M, Zoernig I, Benner A, Spille A, Pommerencke T, von Knebel DM, Folprecht G, Luber B, Feyen N, Martens UM, Beckhove P, Gnjatic S, Schirmacher P, Herpel E, Weitz J, Grabe N, Jaeger D (2011) Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res 71:5670–5677

    Article  CAS  PubMed  Google Scholar 

  206. Zitvogel L, Kroemer G (2015) Subversion of anticancer immunosurveillance by radiotherapy. Nat Immunol 16:1005–1007

    Article  CAS  PubMed  Google Scholar 

  207. Vacchelli E, Ma Y, Baracco EE, Sistigu A, Enot DP, Pietrocola F, Yang H, Adjemian S, Chaba K, Semeraro M, Signore M, Ninno AD, Lucarini V, Peschiaroli F, Businaro L, Gerardino A, Manic G, Ulas T, Günther P, Schultze JL, Kepp O, Stoll G, Lefebvre C, Mulot C, Castoldi F, Rusakiewicz S, Ladoire S, Apetoh L, Pedro JMB-S, Lucattelli M, Delarasse C, Boige V, Ducreux M, Delaloge S, Borg C, André F, Schiavoni G, Vitale I, Laurent-Puig P, Mattei F, Zitvogel L, Kroemer G (2015) Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1. Science 350:972–978

    Article  CAS  PubMed  Google Scholar 

  208. Berhanu A, Huang J, Alber SM, Watkins SC, Storkus WJ (2006) Combinational FLt3 ligand and granulocyte macrophage colony-stimulating factor treatment promotes enhanced tumor infiltration by dendritic cells and antitumor CD8(+) T-cell cross-priming but is ineffective as a therapy. Cancer Res 66:4895–4903

    Article  CAS  PubMed  Google Scholar 

  209. Miller G, Pillarisetty VG, Shah AB, Lahrs S, DeMatteo RP (2003) Murine Flt3 ligand expands distinct dendritic cells with both tolerogenic and immunogenic properties. J Immunol 170:3554–3564

    Article  CAS  PubMed  Google Scholar 

  210. Palucka K, Banchereau J (2013) Dendritic-cell-based therapeutic cancer vaccines. Immunity 39:38–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank R. Gorczynski for helpful comments and advice. The authors declare no competing financial interests. This work was supported by the Canadian Institutes for Health Research (130438 to M.S.C.), Astellas Canada Inc., and the Toronto General Hospital Transplant Program. M.S.C. is a recipient of CIHR/Astellas Research Chair. M.T. is a recipient of a CIHR training award (121831).

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  1. Toronto General Hospital Research Institute, University Health Network, Peter Munk Building, 11-173, 585 University Ave., Toronto, ON, M5G 2N2, Canada

    Michael Tang, Jun Diao & Mark S. Cattral

  2. Department of Surgery, University of Toronto, Toronto, ON, M5G 2N2, Canada

    Mark S. Cattral

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  1. Michael Tang
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  2. Jun Diao
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Correspondence to Mark S. Cattral.

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Tang, M., Diao, J. & Cattral, M.S. Molecular mechanisms involved in dendritic cell dysfunction in cancer. Cell. Mol. Life Sci. 74, 761–776 (2017). https://doi.org/10.1007/s00018-016-2317-8

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  • DOI: https://doi.org/10.1007/s00018-016-2317-8

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