Transcriptional regulation of myeloid-derived suppressor cells

Journal of Leukocyte Biology

Volumn 98, Issue 6, 2015, Pages 913-922

  Condamine, Thomas ^a   Mastio, Jérôme ^a   Gabrilovich, Dmitry I ^a  

^a WISTAR INSTITUTE   (United States)

Author keywords

Rb1; S100A9; STAT3; STAT6

Indexed keywords

ADENOSINE A2B RECEPTOR; ARGINASE 1; CCAAT ENHANCER BINDING PROTEIN BETA; COLONY STIMULATING FACTOR 1; CRYOPYRIN; CYCLOOXYGENASE 2; GAMMA INTERFERON; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; HISTONE DEACETYLASE 2; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; IMMUNOGLOBULIN J RECOMBINATION SIGNAL SEQUENCE BINDING PROTEIN; INTERFERON CONSENSUS SEQUENCE BINDING PROTEIN; INTERLEUKIN 13; INTERLEUKIN 1BETA; INTERLEUKIN 4; INTERLEUKIN 4 RECEPTOR ALPHA; INTERLEUKIN 6; JANUS KINASE 2; MITOGEN ACTIVATED PROTEIN KINASE; MYELOID DIFFERENTIATION FACTOR 88; MYELOPEROXIDASE; NOTCH RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PROSTAGLANDIN E2; REACTIVE OXYGEN METABOLITE; RETINOBLASTOMA BINDING PROTEIN 1; STAT1 PROTEIN; STAT3 PROTEIN; STAT5 PROTEIN; STAT6 PROTEIN; TRANSCRIPTION FACTOR;

ANGIOGENESIS; AUTOIMMUNITY; CELL DIFFERENTIATION; CELL EXPANSION; CELL INVASION; CYTOTOXIC T LYMPHOCYTE; ENDOPLASMIC RETICULUM STRESS; HUMAN; INFECTION; INFLAMMATION; MYELOID DERIVED SUPPRESSOR CELL; MYELOPOIESIS; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; SUPPRESSOR CELL; TRANSCRIPTION REGULATION; TUMOR CELL; TUMOR IMMUNITY; ANIMAL; BONE MARROW CELL; GENETIC TRANSCRIPTION; IMMUNOLOGY; NEOPLASM; NEOVASCULARIZATION (PATHOLOGY); PATHOLOGY; TUMOR INVASION; VASCULARIZATION;

ANIMALS; HUMANS; MYELOID CELLS; MYELOPOIESIS; NEOPLASM INVASIVENESS; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; TRANSCRIPTION FACTORS; TRANSCRIPTION, GENETIC;

EID: 84948963323     PISSN: 07415400     EISSN: 19383673     Source Type: Journal    
DOI: 10.1189/jlb.4RI0515-204R     Document Type: Review

References (144)

1. Lee, M. Y., Rosse, C. (1982) Depletion of lymphocyte subpopulations in primary and secondary lymphoid organs of mice by a transplanted granulocytosis-inducing mammary carcinoma. Cancer Res. 42, 1255–1260.
2. Tsuchiya, Y., Igarashi, M., Suzuki, R., Kumagai, K. (1988) Production of colony-stimulating factor by tumor cells and the factor-mediated induction of suppressor cells. J. Immunol. 141, 699–708.
3. Gabrilovich, D. I., Bronte, V., Chen, S. H., Colombo, M. P., Ochoa, A., Ostrand-Rosenberg, S., Schreiber, H. (2007) The terminology issue for myeloid-derived suppressor cells. Cancer Res. 67, 425, author reply 426.
4. Goh, C., Narayanan, S., Hahn, Y. S. (2013) Myeloid-derived suppressor cells: the dark knight or the joker in viral infections? Immunol. Rev. 255, 210–221.
5. Verschoor, C. P., Johnstone, J., Millar, J., Dorrington, M. G., Habibagahi, M., Lelic, A., Loeb, M., Bramson, J. L., Bowdish, D. M. (2013) Blood CD33(+)HLA-DR(-) myeloid-derived suppressor cells are increased with age and a history of cancer. J. Leukoc. Biol. 93, 633–637.
6. Hurez, V., Daniel, B. J., Sun, L., Liu, A. J., Ludwig, S. M., Kious, M. J., Thibodeaux, S. R., Pandeswara, S., Murthy, K., Livi, C. B., Wall, S., Brumlik, M. J., Shin, T., Zhang, B., Curiel, T. J. (2012) Mitigating agerelated immune dysfunction heightens the efficacy of tumor immunotherapy in aged mice. Cancer Res. 72, 2089–2099.
7. Haile, L. A., Greten, T. F., Korangy, F. (2012) Immune suppression: the hallmark of myeloid derived suppressor cells. Immunol. Invest. 41, 581–594.
8. Nagaraj, S., Youn, J. I., Gabrilovich, D. I. (2013) Reciprocal relationship between myeloid-derived suppressor cells and T cells. J. Immunol. 191, 17–23.
9. Schouppe, E., Van Overmeire, E., Laoui, D., Keirsse, J., Van Ginderachter, J. A. (2013) Modulation of CD8(+) T-cell activation events by monocytic and granulocytic myeloid-derived suppressor cells. Immunobiology 218, 1385–1391.
10. Talmadge, J. E., Gabrilovich, D. I. (2013) History of myeloid-derived suppressor cells. Nat. Rev. Cancer 13, 739–752.
11. Messmer, M. N., Netherby, C. S., Banik, D., Abrams, S. I. (2015) Tumorinduced myeloid dysfunction and its implications for cancer immunotherapy. Cancer Immunol. Immunother. 64, 1–13.
12. 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.
13. Movahedi, K., Guilliams, M., Van den Bossche, J., Van den Bergh, R., Gysemans, C., Beschin, A., De Baetselier, P., Van Ginderachter, J. A. (2008) Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111, 4233–4244.
14. Youn, J. I., Nagaraj, S., Collazo, M., Gabrilovich, D. I. (2008) Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J. Immunol. 181, 5791–5802.
15. Damuzzo, V., Pinton, L., Desantis, G., Solito, S., Marigo, I., Bronte, V., Mandruzzato, S. (2015) Complexity and challenges in defining myeloidderived suppressor cells. Cytometry B Clin. Cytom. 88, 77–91.
16. Youn, J. I., Collazo, M., Shalova, I. N., Biswas, S. K., Gabrilovich, D. I. (2012) Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J. Leukoc. Biol. 91, 167–181.
17. Gabrilovich, D. I., Ostrand-Rosenberg, S., Bronte, V. (2012) Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268.
18. Bayne, L. J., Beatty, G. L., Jhala, N., Clark, C. E., Rhim, A. D., Stanger, B. Z., Vonderheide, R. H. (2012) Tumor-derived granulocytemacrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21, 822–835.
19. Bronte, V., Chappell, D. B., Apolloni, E., Cabrelle, A., Wang, M., Hwu, P., Restifo, N. P. (1999) Unopposed production of granulocyte-macrophage colony-stimulating factor by tumors inhibits CD8+ T cell responses by dysregulating antigen-presenting cell maturation. J. Immunol. 162, 5728–5737.
20. Dolcetti, L., Peranzoni, E., Ugel, S., Marigo, I., Fernandez Gomez, A., Mesa, C., Geilich, M., Winkels, G., Traggiai, E., Casati, A., Grassi, F., Bronte, V. (2010) Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur. J. Immunol. 40, 22–35.
21. Morales, J. K., Kmieciak, M., Knutson, K. L., Bear, H. D., Manjili, M. H. (2010) GM-CSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11b-Gr1- bone marrow progenitor cells into myeloid-derived suppressor cells. Breast Cancer Res. Treat. 123, 39–49.
22. Kowanetz, M., Wu, X., Lee, J., Tan, M., Hagenbeek, T., Qu, X., Yu, L., Ross, J., Korsisaari, N., Cao, T., Bou-Reslan, H., Kallop, D., Weimer, R., Ludlam, M. J., Kaminker, J. S., Modrusan, Z., van Bruggen, N., Peale, F. V., Carano, R., Meng, Y. G., Ferrara, N. (2010) Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc. Natl. Acad. Sci. USA 107, 21248–21255.
23. Okazaki, T., Ebihara, S., Asada, M., Kanda, A., Sasaki, H., Yamaya, M. (2006) Granulocyte colony-stimulating factor promotes tumor angiogenesis via increasing circulating endothelial progenitor cells and Gr1+CD11b+ cells in cancer animal models. Int. Immunol. 18, 1–9.
24. Waight, J. D., Hu, Q., Miller, A., Liu, S., Abrams, S. I. (2011) Tumorderived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism. PLoS One 6, e27690.
25. Kusmartsev, S., Cheng, F., Yu, B., Nefedova, Y., Sotomayor, E., Lush, R., Gabrilovich, D. (2003) All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res. 63, 4441–4449.
26. Menetrier-Caux, C., Montmain, G., Dieu, M. C., Bain, C., Favrot, M. C., Caux, C., Blay, J. Y. (1998) Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood 92, 4778–4791.
27. Condamine, T., Gabrilovich, D. I. (2011) Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol. 32, 19–25.
28. Gabrilovich, D. I., Nagaraj, S. (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174.
29. Condamine, T., Ramachandran, I., Youn, J. I., Gabrilovich, D. I. (2015) Regulation of tumor metastasis by myeloid-derived suppressor cells. Annu. Rev. Med. 66, 97–110.
30. 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.
31. Rébé, C., Végran, F., Berger, H., Ghiringhelli, F. (2013) STAT3 activation: a key factor in tumor immunoescape. JAK-STAT 2, e23010.
32. Yu, H., Liu, Y., McFarland, B. C., Deshane, J. S., Hurst, D. R., Ponnazhagan, S., Benveniste, E. N., Qin, H. (2015) SOCS3 deficiency in myeloid cells promotes tumor development: involvement of STAT3 activation and myeloid-derived suppressor cells. Cancer Immunol. Res. 3, 727–740.
33. Marigo, I., Bosio, E., Solito, S., Mesa, C., Fernandez, A., Dolcetti, L., Ugel, S., Sonda, N., Bicciato, S., Falisi, E., Calabrese, F., Basso, G., Zanovello, P., Cozzi, E., Mandruzzato, S., Bronte, V. (2010) Tumorinduced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity 32, 790–802.
34. Lechner, M. G., Liebertz, D. J., Epstein, A. L. (2010) Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. J. Immunol. 185, 2273–2284.
35. Wu, L., Yan, C., Czader, M., Foreman, O., Blum, J. S., Kapur, R., Du, H. (2012) Inhibition of PPARg in myeloid-lineage cells induces systemic inflammation, immunosuppression, and tumorigenesis. Blood 119, 115–126.
36. Chen, M. F., Kuan, F. C., Yen, T. C., Lu, M. S., Lin, P. Y., Chung, Y. H., Chen, W. C., Lee, K. D. (2014) IL-6-stimulated CD11b+ CD14+ HLADR2 myeloid-derived suppressor cells, are associated with progression and poor prognosis in squamous cell carcinoma of the esophagus. Oncotarget 5, 8716–8728.
37. Oh, K., Lee, O. Y., Shon, S. Y., Nam, O., Ryu, P. M., Seo, M. W., Lee, D. S. (2013) A mutual activation loop between breast cancer cells and myeloidderived suppressor cells facilitates spontaneous metastasis through IL-6 trans-signaling in a murine model. Breast Cancer Res. 15, R79.
38. Wu, C. T., Hsieh, C. C., Lin, C. C., Chen, W. C., Hong, J. H., Chen, M. F. (2012) Significance of IL-6 in the transition of hormone-resistant prostate cancer and the induction of myeloid-derived suppressor cells. J. Mol. Med. 90, 1343–1355.
39. Yen, B. L., Yen, M. L., Hsu, P. J., Liu, K. J., Wang, C. J., Bai, C. H., Sytwu, H. K. (2013) Multipotent human mesenchymal stromal cells mediate expansion of myeloid-derived suppressor cells via hepatocyte growth factor/c-met and STAT3. Stem Cell Rep. 1, 139–151.
40. Lee, J. M., Kim, E. K., Seo, H., Jeon, I., Chae, M. J., Park, Y. J., Song, B., Kim, Y. S., Kim, Y. J., Ko, H. J., Kang, C. Y. (2014) Serum amyloid A3 exacerbates cancer by enhancing the suppressive capacity of myeloidderived suppressor cells via TLR2-dependent STAT3 activation. Eur. J. Immunol. 44, 1672–1684.
41. Liu, Y., Xiang, X., Zhuang, X., Zhang, S., Liu, C., Cheng, Z., Michalek, S., Grizzle, W., Zhang, H. G. (2010) Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. Am. J. Pathol. 176, 2490–2499.
42. Xiang, X., Liu, Y., Zhuang, X., Zhang, S., Michalek, S., Taylor, D. D., Grizzle, W., Zhang, H. G. (2010) TLR2-mediated expansion of MDSCs is dependent on the source of tumor exosomes. Am. J. Pathol. 177, 1606–1610.
43. Buzzelli, J. N., Pavlic, D. I., Chalinor, H. V., O’Connor, L., Menheniott, T. R., Giraud, A. S., Judd, L. M. (2015) IL-1RT1 signaling antagonizes IL-11 induced STAT3 dependent cardiac and antral stomach tumor development through myeloid cell enrichment. Oncotarget 6, 679–695.
44. Yan, D., Yang, Q., Shi, M., Zhong, L., Wu, C., Meng, T., Yin, H., Zhou, J. (2013) Polyunsaturated fatty acids promote the expansion of myeloidderived suppressor cells by activating the JAK/STAT3 pathway. Eur. J. Immunol. 43, 2943–2955.
45. Nefedova, Y., Nagaraj, S., Rosenbauer, A., Muro-Cacho, C., Sebti, S. M., Gabrilovich, D. I. (2005) Regulation of dendritic cell differentiation and antitumor immune response in cancer by pharmacologic-selective inhibition of the janus-activated kinase 2/signal transducers and activators of transcription 3 pathway. Cancer Res. 65, 9525–9535.
46. Fujita, M., Zhu, X., Sasaki, K., Ueda, R., Low, K. L., Pollack, I. F., Okada, H. (2008) Inhibition of STAT3 promotes the efficacy of adoptive transfer therapy using type-1 CTLs by modulation of the immunological microenvironment in a murine intracranial glioma. J. Immunol. 180, 2089–2098.
47. Yang, F., Hu, M., Lei, Q., Xia, Y., Zhu, Y., Song, X., Li, Y., Jie, H., Liu, C., Xiong, Y., Zuo, Z., Zeng, A., Li, Y., Yu, L., Shen, G., Wang, D., Xie, Y., Ye, T., Wei, Y. (2015) Nifuroxazide induces apoptosis and impairs pulmonary metastasis in breast cancer model. Cell Death Dis. 6, e1701.
48. Ye, T., Xiong, Y., Yan, Y., Xia, Y., Song, X., Liu, L., Li, D., Wang, N., Zhang, L., Zhu, Y., Zeng, J., Wei, Y., Yu, L. (2014) The anthelmintic drug niclosamide induces apoptosis, impairs metastasis and reduces immunosuppressive cells in breast cancer model. PLoS One 9, e85887.
49. Yuan, H., Cai, P., Li, Q., Wang, W., Sun, Y., Xu, Q., Gu, Y. (2014) Axitinib augments antitumor activity in renal cell carcinoma via STAT3- dependent reversal of myeloid-derived suppressor cell accumulation. Biomed. Pharmacother. 68, 751–756.
50. Xin, H., Zhang, C., Herrmann, A., Du, Y., Figlin, R., Yu, H. (2009) Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Res. 69, 2506–2513.
51. Ko, J. S., Rayman, P., Ireland, J., Swaidani, S., Li, G., Bunting, K. D., Rini, B., Finke, J. H., Cohen, P. A. (2010) Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Res. 70, 3526–3536.
52. Finke, J., Ko, J., Rini, B., Rayman, P., Ireland, J., Cohen, P. (2011) MDSC as a mechanism of tumor escape from sunitinib mediated antiangiogenic therapy. Int. Immunopharmacol. 11, 856–861.
53. Abad, C., Nobuta, H., Li, J., Kasai, A., Yong, W. H., Waschek, J. A. (2014) Targeted STAT3 disruption in myeloid cells alters immunosuppressor cell abundance in a murine model of spontaneous medulloblastoma. J. Leukoc. Biol. 95, 357–367.
54. Tu, S. P., Jin, H., Shi, J. D., Zhu, L. M., Suo, Y., Lu, G., Liu, A., Wang, T. C., Yang, C. S. (2012) Curcumin induces the differentiation of myeloidderived suppressor cells and inhibits their interaction with cancer cells and related tumor growth. Cancer Prev. Res. (Phila.) 5, 205–215.
55. 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.
56. Chalmin, F., Ladoire, S., Mignot, G., Vincent, J., Bruchard, M., Remy- Martin, J. P., 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 tumorderived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J. Clin. Invest. 120, 457–471.
57. Corzo, C. A., Cotter, M. J., Cheng, P., Cheng, F., Kusmartsev, S., Sotomayor, E., Padhya, T., McCaffrey, T. V., McCaffrey, J. C., Gabrilovich, D. I. (2009) Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J. Immunol. 182, 5693–5701.
58. Cheng, P., Corzo, C. A., Luetteke, N., Yu, B., Nagaraj, S., Bui, M. M., Ortiz, M., Nacken, W., Sorg, C., Vogl, T., Roth, J., Gabrilovich, D. I. (2008) Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J. Exp. Med. 205, 2235–2249.
59. Abrams, S. I. (2010) A multi-functional role of interferon regulatory factor-8 in solid tumor and myeloid cell biology. Immunol. Res. 46, 59–71.
60. Savitsky, D., Tamura, T., Yanai, H., Taniguchi, T. (2010) Regulation of immunity and oncogenesis by the IRF transcription factor family. Cancer Immunol. Immunother. 59, 489–510.
61. Tamura, T., Kurotaki, D., Koizumi, S. I. (2015) Regulation of myelopoiesis by the transcription factor IRF8. Int. J. Hematol. 101, 342–351.
62. Wang, H., Yan, M., Sun, J., Jain, S., Yoshimi, R., Abolfath, S. M., Ozato, K., Coleman, Jr., W. G., Ng, A. P., Metcalf, D., DiRago, L., Nutt, S. L., Morse H. C. (2014) A reporter mouse reveals lineage-specific and heterogeneous expression of IRF8 during lymphoid and myeloid cell differentiation. J. Immunol. 193, 1766–1777.
63. Yáñez, A., Ng, M. Y., Hassanzadeh-Kiabi, N., Goodridge, H. S. (2015) IRF8 acts in lineage-committed rather than oligopotent progenitors to control neutrophil vs monocyte production. Blood 125, 1452–1459.
64. Kurotaki, D., Yamamoto, M., Nishiyama, A., Uno, K., Ban, T., Ichino, M., Sasaki, H., Matsunaga, S., Yoshinari, M., Ryo, A., Nakazawa, M., Ozato, K., Tamura, T. (2014) IRF8 inhibits C/EBPa activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils. Nat. Commun. 5, 4978.
65. Holtschke, T., Löhler, J., Kanno, Y., Fehr, T., Giese, N., Rosenbauer, F., Lou, J., Knobeloch, K. P., Gabriele, L., Waring, J. F., Bachmann, M. F., Zinkernagel, R. M., Morse H. C., Ozato, K., Horak, I. (1996) Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell 87, 307–317.
66. Mattei, F., Schiavoni, G., Sestili, P., Spadaro, F., Fragale, A., Sistigu, A., Lucarini, V., Spada, M., Sanchez, M., Scala, S., Battistini, A., Belardelli, F., Gabriele, L. (2012) IRF-8 controls melanoma progression by regulating the cross talk between cancer and immune cells within the tumor microenvironment. Neoplasia 14, 1223–1235.
67. Paschall, A. V., Zhang, R., Qi, C. F., Bardhan, K., Peng, L., Lu, G., Yang, J., Merad, M., McGaha, T., Zhou, G., Mellor, A., Abrams, S. I., Morse H. C., Ozato, K., Xiong, H., Liu, K. (2015) IFN regulatory factor 8 represses GM-CSF expression in T cells to affect myeloid cell lineage differentiation. J. Immunol. 194, 2369–2379.
68. Hu, X., Bardhan, K., Paschall, A. V., Yang, D., Waller, J. L., Park, M. A., Nayak-Kapoor, A., Samuel, T. A., Abrams, S. I., Liu, K. (2013) Deregulation of apoptotic factors Bcl-xL and Bax confers apoptotic resistance to myeloid-derived suppressor cells and contributes to their persistence in cancer. J. Biol. Chem. 288, 19103–19115.
69. Stewart, T. J., Greeneltch, K. M., Reid, J. E., Liewehr, D. J., Steinberg, S. M., Liu, K., Abrams, S. I. (2009) Interferon regulatory factor-8 modulates the development of tumour-induced CD11b+Gr-1+ myeloid cells. J. Cell. Mol. Med. 13, 3939–3950.
70. Waight, J. D., Netherby, C., Hensen, M. L., Miller, A., Hu, Q., Liu, S., Bogner, P. N., Farren, M. R., Lee, K. P., Liu, K., Abrams, S. I. (2013) Myeloid-derived suppressor cell development is regulated by a STAT/ IRF-8 axis. J. Clin. Invest. 123, 4464–4478.
71. Stewart, T. J., Liewehr, D. J., Steinberg, S. M., Greeneltch, K. M., Abrams, S. I. (2009) Modulating the expression of IFN regulatory factor 8 alters the protumorigenic behavior of CD11b+Gr-1+ myeloid cells. J. Immunol. 183, 117–128.
72. Papaspyridonos, M., Matei, I., Huang, Y., do Rosario Andre, M., Brazier- Mitouart, H., Waite, J. C., Chan, A. S., Kalter, J., Ramos, I., Wu, Q., Williams, C., Wolchok, J. D., Chapman, P. B., Peinado, H., Anandasabapathy, N., Ocean, A. J., Kaplan, R. N., Greenfield, J. P., Bromberg, J., Skokos, D., Lyden, D. (2015) Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation. Nat. Commun. 6, 6840.
73. Ramji, D. P., Foka, P. (2002) CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem. J. 365, 561–575.
74. Nerlov, C. (2007) The C/EBP family of transcription factors: a paradigm for interaction between gene expression and proliferation control. Trends Cell Biol. 17, 318–324.
75. Huber, R., Pietsch, D., Günther, J., Welz, B., Vogt, N., Brand, K. (2014) Regulation of monocyte differentiation by specific signaling modules and associated transcription factor networks. Cell. Mol. Life Sci. 71, 63–92.
76. Manz, M. G., Boettcher, S. (2014) Emergency granulopoiesis. Nat. Rev. Immunol. 14, 302–314.
77. Burkhart, D. L., Sage, J. (2008) Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat. Rev. Cancer 8, 671–682.
78. Genovese, C., Trani, D., Caputi, M., Claudio, P. P. (2006) Cell cycle control and beyond: emerging roles for the retinoblastoma gene family. Oncogene 25, 5201–5209.
79. Youn, J. I., Kumar, V., Collazo, M., Nefedova, Y., Condamine, T., Cheng, P., Villagra, A., Antonia, S., McCaffrey, J. C., Fishman, M., Sarnaik, A., Horna, P., Sotomayor, E., Gabrilovich, D. I. (2013) Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat. Immunol. 14, 211–220.
80. Casbon, A. J., Reynaud, D., Park, C., Khuc, E., Gan, D. D., Schepers, K., Passegué, E., Werb, Z. (2015) Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc. Natl. Acad. Sci. USA 112, E566–E575.
81. Cheng, P., Kumar, V., Liu, H., Youn, J. I., Fishman, M., Sherman, S., Gabrilovich, D. (2014) Effects of Notch signaling on regulation of myeloid cell differentiation in cancer. Cancer Res. 74, 141–152.
82. Yumimoto, K., Akiyoshi, S., Ueo, H., Sagara, Y., Onoyama, I., Ueo, H., Ohno, S., Mori, M., Mimori, K., Nakayama, K. I. (2015) F-Box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner. J. Clin. Invest. 125, 621–635.
83. Chen, J. F., Eltzschig, H. K., Fredholm, B. B. (2013) Adenosine receptors as drug targets–what are the challenges? Nat. Rev. 12, 265–286.
84. Ryzhov, S., Novitskiy, S. V., Goldstein, A. E., Biktasova, A., Blackburn, M. R., Biaggioni, I., Dikov, M. M., Feoktistov, I. (2011) Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b+Gr1+ cells. J. Immunol. 187, 6120–6129.
85. Iannone, R., Miele, L., Maiolino, P., Pinto, A., Morello, S. (2013) Blockade of A2b adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma. Neoplasia 15, 1400–1409.
86. Saxena, M., Yeretssian, G. (2014) NOD-like receptors: master regulators of inflammation and cancer. Front. Immunol. 5, 327.
87. Vanaja, S. K., Rathinam, V. A., Fitzgerald, K. A. (2015) Mechanisms of inflammasome activation: recent advances and novel insights. Trends Cell Biol. 25, 308–315.
88. Van Deventer, H. W., Burgents, J. E., Wu, Q. P., Woodford, R. M., Brickey, W. J., Allen, I. C., McElvania-Tekippe, E., Serody, J. S., Ting, J. P. (2010) The inflammasome component NLRP3 impairs antitumor vaccine by enhancing the accumulation of tumor-associated myeloidderived suppressor cells. Cancer Res. 70, 10161–10169.
89. Chow, M. T., Sceneay, J., Paget, C., Wong, C. S., Duret, H., Tschopp, J., Möller, A., Smyth, M. J. (2012) NLRP3 suppresses NK cell-mediated responses to carcinogen-induced tumors and metastases. Cancer Res. 72, 5721–5732.
90. Youn, J. I., Gabrilovich, D. I. (2010) The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur. J. Immunol. 40, 2969–2975.
91. Li, H., Han, Y., Guo, Q., Zhang, M., Cao, X. (2009) Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J. Immunol. 182, 240–249.
92. Arora, M., Poe, S. L., Oriss, T. B., Krishnamoorthy, N., Yarlagadda, M., Wenzel, S. E., Billiar, T. R., Ray, A., Ray, P. (2010) TLR4/MyD88- induced CD11b+Gr-1 int F4/80+ non-migratory myeloid cells suppress Th2 effector function in the lung. Mucosal Immunol. 3, 578–593.
93. Bunt, S. K., Clements, V. K., Hanson, E. M., Sinha, P., Ostrand-Rosenberg, S. (2009) Inflammation enhances myeloid-derived suppressor cell cross-talk by signaling through Toll-like receptor 4. J. Leukoc. Biol. 85, 996–1004.
94. Hong, E. H., Chang, S. Y., Lee, B. R., Kim, Y. S., Lee, J. M., Kang, C. Y., Kweon, M. N., Ko, H. J. (2013) Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid-derived suppressor cells. Int. J. Cancer 132, 2839–2848.
95. Diao, J., Yang, X., Song, X., Chen, S., He, Y., Wang, Q., Chen, G., Luo, C., Wu, X., Zhang, Y. (2015) Exosomal Hsp70 mediates immunosuppressive activity of the myeloid-derived suppressor cells via phosphorylation of Stat3. Med. Oncol. 32, 453.
96. Wu, H., Tao, N., Liu, X., Li, X., Tang, J., Ma, C., Xu, X., Shao, H., Hou, B., Wang, H., Qin, Z. (2012) Polysaccharide from Lentinus edodes inhibits the immunosuppressive function of myeloid-derived suppressor cells. PLoS One 7, e51751.
97. Yang, Y., Zhang, R., Xia, F., Zou, T., Huang, A., Xiong, S., Zhang, J. (2013) LPS converts Gr-1(+)CD115(+) myeloid-derived suppressor cells from M2 to M1 via P38 MAPK. Exp. Cell Res. 319, 1774–1783.
98. Tu, S., Bhagat, G., Cui, G., Takaishi, S., Kurt-Jones, E. A., Rickman, B., Betz, K. S., Penz-Oesterreicher, M., Bjorkdahl, O., Fox, J. G., Wang, T. C. (2008) Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 14, 408–419.
99. Elkabets, M., Ribeiro, V. S., Dinarello, C. A., Ostrand-Rosenberg, S., Di Santo, J. P., Apte, R. N., Vosshenrich, C. A. (2010) IL-1b regulates a novel myeloid-derived suppressor cell subset that impairs NK cell development and function. Eur. J. Immunol. 40, 3347–3357.
100. Lu, T., Ramakrishnan, R., Altiok, S., Youn, J. I., Cheng, P., Celis, E., Pisarev, V., Sherman, S., Sporn, M. B., Gabrilovich, D. (2011) Tumorinfiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J. Clin. Invest. 121, 4015–4029.
101. Hu, X., Li, B., Li, X., Zhao, X., Wan, L., Lin, G., Yu, M., Wang, J., Jiang, X., Feng, W., Qin, Z., Yin, B., Li, Z. (2014) Transmembrane TNF-a promotes suppressive activities of myeloid-derived suppressor cells via TNFR2. J. Immunol. 192, 1320–1331.
102. Sade-Feldman, M., Kanterman, J., Ish-Shalom, E., Elnekave, M., Horwitz, E., Baniyash, M. (2013) Tumor necrosis factor-a blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation. Immunity 38, 541–554.
103. Polz, J., Remke, A., Weber, S., Schmidt, D., Weber-Steffens, D., Pietryga-Krieger, A., Müller, N., Ritter, U., Mostböck, S., Männel, D. N. (2014) Myeloid suppressor cells require membrane TNFR2 expression for suppressive activity. Immun. Inflamm. Dis. 2, 121–130.
104. Zhao, X., Rong, L., Zhao, X., Li, X., Liu, X., Deng, J., Wu, H., Xu, X., Erben, U., Wu, P., Syrbe, U., Sieper, J., Qin, Z. (2012) TNF signaling drives myeloidderived suppressor cell accumulation. J. Clin. Invest. 122, 4094–4104.
105. Gallina, G., Dolcetti, L., Serafini, P., De Santo, C., Marigo, I., Colombo, M. P., Basso, G., Brombacher, F., Borrello, I., Zanovello, P., Bicciato, S., Bronte, V. (2006) Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J. Clin. Invest. 116, 2777–2790.
106. Kusmartsev, S., Gabrilovich, D. I. (2005) STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J. Immunol. 174, 4880–4891.
107. Schouppe, E., Mommer, C., Movahedi, K., Laoui, D., Morias, Y., Gysemans, C., Luyckx, A., De Baetselier, P., Van Ginderachter, J. A. (2013) Tumor-induced myeloid-derived suppressor cell subsets exert either inhibitory or stimulatory effects on distinct CD8+ T-cell activation events. Eur. J. Immunol. 43, 2930–2942.
108. Medina-Echeverz, J., Haile, L. A., Zhao, F., Gamrekelashvili, J., Ma, C., Métais, J. Y., Dunbar, C. E., Kapoor, V., Manns, M. P., Korangy, F., Greten, T. F. (2014) IFN-g regulates survival and function of tumor-induced CD11b+ Gr-1high myeloid derived suppressor cells by modulating the anti-apoptotic molecule Bcl2a1. Eur. J. Immunol. 44, 2457–2467.
109. Sinha, P., Parker, K. H., Horn, L., Ostrand-Rosenberg, S. (2012) Tumorinduced myeloid-derived suppressor cell function is independent of IFN-g and IL-4Ra. Eur. J. Immunol. 42, 2052–2059.
110. Bronte, V., Serafini, P., De Santo, C., Marigo, I., Tosello, V., Mazzoni, A., Segal, D. M., Staib, C., Lowel, M., Sutter, G., Colombo, M. P., Zanovello, P. (2003) IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J. Immunol. 170, 270–278.
111. Sinha, P., Clements, V. K., Ostrand-Rosenberg, S. (2005) Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease. J. Immunol. 174, 636–645.
112. Sinha, P., Clements, V. K., Ostrand-Rosenberg, S. (2005) Interleukin-13- regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis. Cancer Res. 65, 11743–11751.
113. Kohanbash, G., McKaveney, K., Sakaki, M., Ueda, R., Mintz, A. H., Amankulor, N., Fujita, M., Ohlfest, J. R., Okada, H. (2013) GM-CSF promotes the immunosuppressive activity of glioma-infiltrating myeloid cells through interleukin-4 receptor-a. Cancer Res. 73, 6413–6423.
114. Terabe, M., Matsui, S., Park, J. M., Mamura, M., Noben-Trauth, N., Donaldson, D. D., Chen, W., Wahl, S. M., Ledbetter, S., Pratt, B., Letterio, J. J., Paul, W. E., Berzofsky, J. A. (2003) Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocytemediated tumor immunosurveillance: abrogation prevents tumor recurrence. J. Exp. Med. 198, 1741–1752.
115. Highfill, S. L., Rodriguez, P. C., Zhou, Q., Goetz, C. A., Koehn, B. H., Veenstra, R., Taylor, P. A., Panoskaltsis-Mortari, A., Serody, J. S., Munn, D. H., Tolar, J., Ochoa, A. C., Blazar, B. R. (2010) Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is upregulated by interleukin-13. Blood 116, 5738–5747.
116. Munera, V., Popovic, P. J., Bryk, J., Pribis, J., Caba, D., Matta, B. M., Zenati, M., Ochoa, J. B. (2010) Stat 6-dependent induction of myeloid derived suppressor cells after physical injury regulates nitric oxide response to endotoxin. Ann. Surg. 251, 120–126.
117. Roth, F., De La Fuente, A. C., Vella, J. L., Zoso, A., Inverardi, L., Serafini, P. (2012) Aptamer-mediated blockade of IL4Ra triggers apoptosis of MDSCs and limits tumor progression. Cancer Res. 72, 1373–1383.
118. Rodriguez, P. C., Hernandez, C. P., Quiceno, D., Dubinett, S. M., Zabaleta, J., Ochoa, J. B., Gilbert, J., Ochoa, A. C. (2005) Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J. Exp. Med. 202, 931–939.
119. Donkor, M. K., Lahue, E., Hoke, T. A., Shafer, L. R., Coskun, U., Solheim, J. C., Gulen, D., Bishay, J., Talmadge, J. E. (2009) Mammary tumor heterogeneity in the expansion of myeloid-derived suppressor cells. Int. Immunopharmacol. 9, 937–948.
120. Obermajer, N., Muthuswamy, R., Lesnock, J., Edwards, R. P., Kalinski, P. (2011) Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood 118, 5498–5505.
121. Obermajer, N., Kalinski, P. (2012) Generation of myeloid-derived suppressor cells using prostaglandin E2. Transplant. Res. 1, 15.
122. Mao, Y., Poschke, I., Wennerberg, E., Pico de Coaña, Y., Egyhazi Brage, S., Schultz, I., Hansson, J., Masucci, G., Lundqvist, A., Kiessling, R. (2013) Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. Cancer Res. 73, 3877–3887.
123. Mao, Y., Sarhan, D., Steven, A., Seliger, B., Kiessling, R., Lundqvist, A. (2014) Inhibition of tumor-derived prostaglandin-e2 blocks the induction of myeloid-derived suppressor cells and recovers natural killer cell activity. Clin. Cancer Res. 20, 4096–4106.
124. Fujita, M., Kohanbash, G., Fellows-Mayle, W., Hamilton, R. L., Komohara, Y., Decker, S. A., Ohlfest, J. R., Okada, H. (2011) COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells. Cancer Res. 71, 2664–2674.
125. Veltman, J. D., Lambers, M. E., van Nimwegen, M., Hendriks, R. W., Hoogsteden, H. C., Aerts, J. G., Hegmans, J. P. (2010) COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function. BMC Cancer 10, 464.
126. Sinha, P., Clements, V. K., Fulton, A. M., Ostrand-Rosenberg, S. (2007) Prostaglandin E2 promotes tumor progression by inducing myeloidderived suppressor cells. Cancer Res. 67, 4507–4513.
127. Obermajer, N., Muthuswamy, R., Odunsi, K., Edwards, R. P., Kalinski, P. (2011) PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res. 71, 7463–7470.
128. Obermajer, N., Wong, J. L., Edwards, R. P., Odunsi, K., Moysich, K., Kalinski, P. (2012) PGE(2)-driven induction and maintenance of cancer-associated myeloid-derived suppressor cells. Immunol. Invest. 41, 635–657.
129. Holcik, M., Sonenberg, N. (2005) Translational control in stress and apoptosis. Nat. Rev. Mol. Cell Biol. 6, 318–327.
130. Ron, D., Walter, P. (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529.
131. Cláudio, N., Dalet, A., Gatti, E., Pierre, P. (2013) Mapping the crossroads of immune activation and cellular stress response pathways. EMBO J. 32, 1214–1224.
132. Bettigole, S. E., Glimcher, L. H. (2015) Endoplasmic reticulum stress in immunity. Annu. Rev. Immunol. 33, 107–138.
133. Zhang, K., Kaufman, R. J. (2008) From endoplasmic-reticulum stress to the inflammatory response. Nature 454, 455–462.
134. Mahadevan, N. R., Anufreichik, V., Rodvold, J. J., Chiu, K. T., Sepulveda, H., Zanetti, M. (2012) Cell-extrinsic effects of tumor ER stress imprint myeloid dendritic cells and impair CD8⁺ T cell priming. PLoS One 7, e51845.
135. Mahadevan, N. R., Rodvold, J., Sepulveda, H., Rossi, S., Drew, A. F., Zanetti, M. (2011) Transmission of endoplasmic reticulum stress and pro-inflammation from tumor cells to myeloid cells. Proc. Natl. Acad. Sci. USA 108, 6561–6566.
136. Mahadevan, N. R., Zanetti, M. (2011) Tumor stress inside out: cellextrinsic effects of the unfolded protein response in tumor cells modulate the immunological landscape of the tumor microenvironment. J. Immunol. 187, 4403–4409.
137. Condamine, T., Kumar, V., Ramachandran, I. R., Youn, J. I., Celis, E., Finnberg, N., El-Deiry, W. S., Winograd, R., Vonderheide, R. H., English, N. R., Knight, S. C., Yagita, H., McCaffrey, J. C., Antonia, S., Hockstein, N., Witt, R., Masters, G., Bauer, T., Gabrilovich, D. I. (2014) ER stress regulates myeloid-derived suppressor cell fate through TRAILR- mediated apoptosis. J. Clin. Invest. 124, 2626–2639.
138. Lee, B.R., Chang, S. Y., Hong, E. H., Kwon, B. E., Kim, H.M., Kim, Y. J., Lee, J., Cho, H. J., Cheon, J. H., Ko, H. J. (2014) Elevated endoplasmic reticulum stress reinforced immunosuppression in the tumor microenvironment via myeloid-derived suppressor cells. Oncotarget 5, 12331–12345.
139. Thevenot, P. T., Sierra, R. A., Raber, P. L., Al-Khami, A. A., Trillo-Tinoco, J., Zarreii, P., Ochoa, A. C., Cui, Y., Del Valle, L., Rodriguez, P. C. (2014) The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors. Immunity 41, 389–401.
140. Condamine, T., Gabrilovich, D. I. (2014) Can the suppressive activity of myeloid-derived suppressor cells be “chop”ped? Immunity 41, 341–342.
141. Zeng, L., Liu, Y. P., Sha, H., Chen, H., Qi, L., Smith, J. A. (2010) XBP-1 couples endoplasmic reticulum stress to augmented IFN-beta induction via a cis-acting enhancer in macrophages. J. Immunol. 185, 2324–2330.
142. Goodall, J. C., Wu, C., Zhang, Y., McNeill, L., Ellis, L., Saudek, V., Gaston, J. S. (2010) Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. Proc. Natl. Acad. Sci. USA 107, 17698–17703.
143. Liu, Y. P., Zeng, L., Tian, A., Bomkamp, A., Rivera, D., Gutman, D., Barber, G. N., Olson, J. K., Smith, J. A. (2012) Endoplasmic reticulum stress regulates the innate immunity critical transcription factor IRF3. J. Immunol. 189, 4630–4639.
144. Zhao, C., Pavicic, Jr., P. G., Datta, S., Sun, D., Novotny, M., Hamilton, T. A. (2014) Cellular stress amplifies TLR3/4-induced CXCL1/2 gene transcription in mononuclear phagocytes via RIPK1. J. Immunol. 193, 879–888.