PGE2-driven induction and maintenance of cancer-associated myeloid-derived suppressor cells

Immunological Investigations

Volumn 41, Issue 6-7, 2012, Pages 635-657

  Obermajer, Nataša ^a   Wong, Jeffrey L ^b   Edwards, Robert P ^c,d,e   Odunsi, Kunle ^f   Moysich, Kirsten ^f   Kalinski, Pawel ^b,e,g,h  

^a UNIVERSITY OF LJUBLJANA   (Slovenia)

^b UNIVERSITY OF PITTSBURGH MEDICAL CENTER   (United States)

^c UNIVERSITY OF PITTSBURGH   (United States)

^d Peritoneal/Ovarian Cancer Specialty Care Center   (United States)

^e UNIVERSITY OF PITTSBURGH CANCER INSTITUTE   (United States)

^f ROSWELL PARK CANCER INSTITUTE   (United States)

^g UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^h UNIVERSITY OF PITTSBURGH   (United States)

Author keywords

Arginase; Cancer; Chemokines; COX2; Cytokines; Dendritic cells; Immunopathology; Immunosuppression; Immunotherapy; Inducible NOS; Inflammation; Interferons; Macrophages; Myeloid derived suppressor cells; PGE2; Prostaglandins; ROS; Tolerance

Indexed keywords

CD11B ANTIGEN; CD16 ANTIGEN; CD32 ANTIGEN; CYCLOOXYGENASE 2; GAMMA INTERFERON; GAMMA INTERFERON RECEPTOR 1; HYPOXIA INDUCIBLE FACTOR 1; INDUCIBLE NITRIC OXIDE SYNTHASE; INTERLEUKIN 1BETA; INTERLEUKIN 4 RECEPTOR ALPHA; PROSTAGLANDIN E2; PROTEIN KINASE LCK; SCATTER FACTOR; TOLL LIKE RECEPTOR; TRANSFORMING GROWTH FACTOR BETA; ARGINASE; ARGINASE I, HUMAN; ARGININE; CHEMOKINE RECEPTOR CXCR4; CXCL12 PROTEIN, HUMAN; CXCR4 PROTEIN, HUMAN; INDOLEAMINE 2,3 DIOXYGENASE; NOS2 PROTEIN, HUMAN; PTGS2 PROTEIN, HUMAN; STROMAL CELL DERIVED FACTOR 1;

ANTIGEN EXPRESSION; ARTICLE; BONE MARROW CELL; CATABOLISM; CELL CYCLE ARREST; CELL CYCLE G1 PHASE; ENZYME INHIBITION; GRANULOCYTE; HUMAN; IMMUNOREGULATION; MONOCYTE; MYELOID DERIVED SUPPRESSOR CELL; NONHUMAN; PHENOTYPE; PLASTICITY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN METABOLISM; SPLEEN CELL; SUPPRESSOR CELL; TUMOR IMMUNITY; UPREGULATION; ANIMAL; GENETICS; IMMUNOLOGY; METABOLISM; MOUSE; MYELOID PROGENITOR CELL; NEOPLASM; PATHOLOGY; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE;

ANIMALS; ARGINASE; ARGININE; CHEMOKINE CXCL12; CYCLOOXYGENASE 2; DINOPROSTONE; HUMANS; INDOLEAMINE-PYRROLE 2,3,-DIOXYGENASE; MICE; MYELOID PROGENITOR CELLS; NEOPLASMS; NITRIC OXIDE SYNTHASE TYPE II; RECEPTORS, CXCR4; SIGNAL TRANSDUCTION; T-LYMPHOCYTES;

EID: 84866939221     PISSN: 08820139     EISSN: 15324311     Source Type: Journal    
DOI: 10.3109/08820139.2012.695417     Document Type: Article

References (153)

1. Almand, B., Clark, J.I., Nikitina, E., van Beynen, J., English, N.R., Knight, S.C., Carbone,D.P., and Gabrilovich, D.I. (2001). Increased production of immature myeloid cells incancer patients: a mechanism of immunosuppression in cancer. J. Immunol.166: 678-689.
2. Bankhurst, A.D. (1982). The modulation of human natural killer cell activity by prostaglandins.J. Clin. Lab. Immunol. 7: 85-91.
3. Baratelli, F., Lin, Y., Zhu, L., Yang, S.C., Heuze-Vourc'h, N., Zeng, G., Reckamp, K.,Dohadwala, M., Sharma, S., Dubinett, S.M. (2005). Prostaglandin E2 inducesFOXP3 gene expression and T regulatory cell function in human CD4 + T cells.J. Immunol. 175: 1483-1490.
4. Basu, G.D., Tinder, T.L., Bradley, J.M., Tu, T., Hattrup, C.L., Pockaj, B.A., andMukherjee, P. (2006). Cyclooxygenase-2 inhibitor enhances the efficacy of a breastcancer vaccine: Role of IDO. J. Immunol. 177: 2391-2402.
5. Bingisser, R.M., Tilbrook, P.A., Holt, P.G., Kees, U.R. (1998). Macrophage-derived nitricoxide regulates T cell activation via reversible disruption of the Jak3/STAT5 signalingpathway. J. Immunol. 160: 5729-5734.
6. Blanco, J.C., Contursi, C., Salkowski, C.A., DeWitt, D.L., Ozato, K., Vogel, S.N. (2000).Interferon regulatory factor (IRF)-1 and IRF-2 regulate interferon gammadependentcyclooxygenase 2 expression. J. Exp. Med. 191: 2131-2144.
7. Bogdan, C. (2001). Nitric oxide and the immune response. Nat. Immunol. 2: 907-916.
8. Braun, D., Longman, R.S., Albert, M.L. (2005). A two-step induction of indoleamine 2,3dioxygenase (IDO) activity during dendritic-cell maturation. Blood 106: 2375-2381.
9. Brecht, K., Weigert, A., Hu, J., Popp, R., Fisslthaler, B., Korff, T., Fleming, I., Geisslinger,G., and Brune, B. (2011). Macrophages programmed by apoptotic cells promoteangiogenesis via prostaglandin E2. FASEB J. 25: 2408-2417.
10. Bronte, V. (2009). Myeloid-derived suppressor cells in inflammation: uncovering cellsubsets with enhanced immunosuppressive functions. Eur. J. Immunol. 39: 2670-2672.
11. Bronte, V., Apolloni, E., Cabrelle, A., Ronca, R., Serafini, P., Zamboni, P., Restifo, N.P.,Zanovello, P. (2000). Identification of a CD11b( +)/Gr-1( +)/CD31( +) myeloid progenitorcapable of activating or suppressing CD8( +) T cells. Blood 96: 3838-3846.
12. Bronte, V., Chappell, D.B., Apolloni, E., Cabrelle, A., Wang, M., Hwu, P., Restifo, N.P.(1999). Unopposed production of granulocyte-macrophage colony-stimulating factorby tumors inhibits CD8 + T cell responses by dysregulating antigen-presenting cellmaturation. J. Immunol. 162: 5728-5737.
13. Bronte, V., Serafini, P., Apolloni, E., Zanovello, P. (2001). Tumor-induced immune dysfunctionscaused by myeloid suppressor cells. J. Immunother. 24: 431-446.
14. Bronte, V., Serafini, P., De Santo, C., Marigo, I., Tosello, V., Mazzoni, A., Segal, D.M.,Staib, C., Lowel, M., Sutter, G., et al. (2003). IL-4-induced arginase 1 suppressesalloreactive T cells in tumor-bearing mice. J. Immunol. 170: 270-278.
15. Bronte, V., Wang, M., Overwijk, W.W., Surman, D.R., Pericle, F., Rosenberg, S.A.,Restifo, N.P. (1998). Apoptotic death of CD8 + T lymphocytes after immunization: induction of a suppressive population of Mac-1 +Gr-1 + cells. J. Immunol. 161: 5313-5320.
16. Bronte, V., Zanovello, P. (2005). Regulation of immune responses by L-arginine metabolism.Nat. Rev. Immunol. 5: 641-654.
17. Byrne, G.I., Lehmann, L.K., Kirschbaum, J.G., Borden, E.C., Lee, C.M., Brown, R.R.(1986). Induction of tryptophan degradation in vitro and in vivo: a gammainterferon-stimulated activity. J. Interferon Res. 6: 389-396.
18. Carmeliet, P., Dor, Y., Herbert, J.M., Fukumura, D., Brusselmans, K., Dewerchin, M.,Neeman, M., Bono, F., Abramovitch, R., Maxwell, P., et al. (1998). Role of HIF-1alphain hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature394: 485-490.
19. Cesario, A., Rocca, B., Rutella, S. (2011). The interplay between indoleamine 2,3-dioxygenase 1 (IDO1) and cyclooxygenase (COX)-2 in chronic inflammation andcancer. Curr. Med. Chem. 18: 2263-2271.
20. Chen, J.H., Wu, C.W., Kao, H.L., Chang, H.M., Li, A.F., Liu, T.Y., Chi, C.W. (2006).Effects of COX-2 inhibitor on growth of human gastric cancer cells and its relationto hepatocyte growth factor. Cancer Lett. 239: 263-270.
21. Chomarat, P., Banchereau, J., Davoust, J., Palucka, A.K. (2000). IL-6 switches thedifferentiation of monocytes from dendritic cells to macrophages. Nat. Immunol.1: 510-514.
22. Chouaib, S., Welte, K., Mertelsmann, R., Dupont, B. (1985). Prostaglandin E2 acts attwo distinct pathways of T lymphocyte activation: inhibition of interleukin 2production and down-regulation of transferrin receptor expression. J. Immunol.135: 1172-1179.
23. Choudhry, M.A., Ahmed, Z., Sayeed, M.M. (1999). PGE(2)-mediated inhibition of T cellp59(fyn) is independent of cAMP. Am. J. Physiol. 277: C302-309.
24. Choudhry, M.A., Uddin, S., Sayeed, M.M. (1998). Prostaglandin E2 modulation of p59fyntyrosine kinase in T lymphocytes during sepsis. J. Immunol. 160: 929-935.
25. Condamine, T., Gabrilovich, D.I. (2011). Molecular mechanisms regulating myeloidderivedsuppressor cell differentiation and function. Trends Immunol. 32: 19-25.
26. Corzo, C.A., Condamine, T., Lu, L., Cotter, M.J., Youn, J.I., Cheng, P., Cho, H.I., Celis, E.,Quiceno, D.G., Padhya, T., et al. (2010). HIF-1alpha regulates function and differentiationof myeloid-derived suppressor cells in the tumor microenvironment.J. Exp. Med. 207: 2439-2453.
27. 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 regulatingreactive oxygen species in tumor-induced myeloid-derived suppressor cells.J. Immunol. 182: 5693-5701.
28. Csiki, I., Yanagisawa, K., Haruki, N., Nadaf, S., Morrow, J.D., Johnson, D.H.,Carbone, D.P. (2006). Thioredoxin-1 modulates transcription of cyclooxygenase-2via hypoxia-inducible factor-1alpha in non-small cell lung cancer. Cancer Res.66: 143-150.
29. Curiel, T.J., Wei, S., Dong, H., Alvarez, X., Cheng, P., Mottram, P., Krzysiek, R., Knutson,K.L., Daniel, B., Zimmermann, M.C., et al. (2003). Blockade of B7-H1 improvesmyeloid dendritic cell-mediated antitumor immunity. Nat. Med. 9: 562-567.
30. Dahiya, Y., Pandey, R.K., Bhatt, K.H., Sodhi, A. (2010). Role of prostaglandin E2 inpeptidoglycan mediated iNOS expression in mouse peritoneal macrophagesin vitro. FEBS Lett. 584: 4227-4232.
31. Delano, M.J., Scumpia, P.O., Weinstein, J.S., Coco, D., Nagaraj, S., Kelly-Scumpia, K.M.,O'Malley, K.A., Wynn, J.L., Antonenko, S., Al-Quran, S.Z., et al. (2007). MyD88-dependent expansion of an immature GR-1( +)CD11b( +) population induces T cellsuppression and Th2 polarization in sepsis. J. Exp. Med. 204: 1463-1474.
32. 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 expansionof myeloid-derived suppressor cells. Int. Immunopharmacol. 9: 937-948.
33. Donnini, S., Finetti, F., Solito, R., Terzuoli, E., Sacchetti, A.,Morbidelli, L., Patrignani, P.,Ziche, M. (2007). EP2 prostanoid receptor promotes squamous cell carcinoma growththrough epidermal growth factor receptor transactivation and iNOS and ERK1/2pathways. FASEB J. 21: 2418-2430.
34. Duhe, R.J., Evans, G.A., Erwin, R.A., Kirken, R.A., Cox, G.W., Farrar, W.L. (1998). Nitricoxide and thiol redox regulation of Janus kinase activity. Proc. Natl. Acad. Sci. USA95: 126-131.
35. Eliopoulos, A.G., Dumitru, C.D., Wang, C.C., Cho, J., Tsichlis, P.N. (2002). Induction ofCOX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activationsignals. EMBO J. 21: 4831-4840.
36. Elkabets, M., Ribeiro, V.S., Dinarello, C.A., Ostrand-Rosenberg, S., Di Santo, J.P., Apte,R.N., Vosshenrich, C.A. (2010). IL-1beta regulates a novel myeloid-derived suppressorcell subset that impairs NK cell development and function. Eur. J. Immunol.40: 3347-3357.
37. Eruslanov, E., Daurkin, I., Ortiz, J., Vieweg, J., Kusmartsev, S. (2010). Pivotal Advance: Tumor-mediated induction of myeloid-derived suppressor cells and M2-polarizedmacrophages by altering intracellular PGE catabolism in myeloid cells.J. Leukocyte Biol. 88: 839-848.
38. Eruslanov, E., Daurkin, I., Vieweg, J., Daaka, Y., Kusmartsev, S. (2011). Aberrant PGEmetabolism in bladder tumor microenvironment promotes immunosuppressive phenotypeof tumor-infiltrating myeloid cells. Int. Immunopharmacol. 11: 848-855.
39. Eruslanov, E., Kaliberov, S., Daurkin, I., Kaliberova, L., Buchsbaum, D., Vieweg, J.,Kusmartsev, S. (2009). Altered expression of 15-hydroxyprostaglandin dehydrogenasein tumor-infiltrated CD11b myeloid cells: a mechanism for immune evasion incancer. J. Immunol. 182: 7548-7557.
40. Fallarino, F., Grohmann, U., You, S., McGrath, B.C., Cavener, D.R., Vacca, C., Orabona,C., Bianchi, R., Belladonna, M.L., Volpi, C., et al. (2006). The combined effects oftryptophan starvation and tryptophan catabolites down-regulate T cell receptorzeta-chain and induce a regulatory phenotype in naive T cells. J. Immunol.176: 6752-6761.
41. Faour, W.H., He, Y.,He, Q.W., de Ladurantaye,M., Quintero, M.,Mancini, A., Di Battista,J.A. (2001). Prostaglandin E(2) regulates the level and stability of cyclooxygenase-2mRNA through activation of p38 mitogen-activated protein kinase in interleukin-1beta-treated human synovial fibroblasts. J. Biol. Chem. 276: 31720-31731.
42. Filipazzi, P., Valenti, R., Huber, V., Pilla, L., Canese, P., Iero, M., Castelli, C., Mariani, L.,Parmiani, G., Rivoltini, L. (2007). Identification of a new subset of myeloid suppressorcells in peripheral blood of melanoma patients with modulation by a granulocytemacrophagecolony-stimulation factor-based antitumor vaccine. J. Clin. Oncol.25: 2546-2553.
43. Fischer, T.A., Palmetshofer, A., Gambaryan, S., Butt, E., Jassoy, C., Walter, U., Sopper,S., Lohmann, S.M. (2001). Activation of cGMP-dependent protein kinase Ibeta inhibitsinterleukin 2 release and proliferation of T cell receptor-stimulated humanperipheral T cells. J. Biol. Chem. 276: 5967-5974.
44. Fujino, H., Salvi, S., Regan, J.W. (2005). Differential regulation of phosphorylation of thecAMP response element-binding protein after activation of EP2 and EP4 prostanoidreceptors by prostaglandin E2. Mol. Pharmacol. 68: 251-259.
45. Fujino, H., West, K.A., Regan, J.W. (2002). Phosphorylation of glycogen synthase kinase-3and stimulation of T-cell factor signaling following activation of EP2 and EP4prostanoid receptors by prostaglandin E2. J. Biol. Chem. 277: 2614-2619.
46. Fujino, H., Xu, W., Regan, J.W. (2003). Prostaglandin E2 induced functional expression ofearly growth response factor-1 by EP4, but not EP2, prostanoid receptors via thephosphatidylinositol 3-kinase and extracellular signal-regulated kinases. J. Biol.Chem. 278: 12151-12156.
47. 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 byinhibiting myeloid-derived suppressor cells. Cancer Res. 71: 2664-2674.
48. Gabrilovich, D. (2004). Mechanisms and functional significance of tumour-induceddendritic-cell defects. Nat. Rev. Immunol. 4: 941-952.
49. Gabrilovich, D., Ishida, T., Oyama, T., Ran, S., Kravtsov, V., Nadaf, S., Carbone, D.P.(1998). Vascular endothelial growth factor inhibits the development of dendritic cellsand dramatically affects the differentiation of multiple hematopoietic lineagesin vivo. Blood 92: 4150-4166.
50. Gabrilovich, D.I., Nagaraj, S. (2009). Myeloid-derived suppressor cells as regulators ofthe immune system. Nat. Rev. Immunol. 9: 162-174.
51. Gallina, G., Dolcetti, L., Serafini, P., De Santo, C., Marigo, I., Colombo, M.P., Basso, G.,Brombacher, F., Borrello, I., Zanovello, P., et al. (2006). Tumors induce a subset ofinflammatory monocytes with immunosuppressive activity on CD8 + T cells. J. Clin.Invest. 116: 2777-2790.
52. Gerlo, S., Verdood, P., Gellersen, B., Hooghe-Peters, E.L., Kooijman, R. (2004).Mechanism of prostaglandin (PG)E2-induced prolactin expression in humanT cells: cooperation of two PGE2 receptor subtypes, E-prostanoid (EP) 3 and EP4,via calcium-and cyclic adenosine 50-monophosphate-mediated signaling pathways.J. Immunol. 173: 5952-5962.
53. Goodwin, J.S., Ceuppens, J. (1983). Regulation of the immune response by prostaglandins.J. Clin. Immunol. 3: 295-315.
54. Goto, T., Herberman, R.B., Maluish, A., Strong, D.M. (1983). Cyclic AMP as a mediator ofprostaglandin E-induced suppression of human natural killer cell activity.J. Immunol. 130: 1350-1355.
55. Greifenberg, V., Ribechini, E., Rossner, S., Lutz, M.B. (2009). Myeloid-derived suppressorcell activation by combined LPS and IFN-gamma treatment impairs DC development.Eur. J. Immunol. 39: 2865-2876.
56. Haas, A.R., Sun, J., Vachani, A., Wallace, A.F., Silverberg, M., Kapoor, V., Albelda, S.M.(2006). Cycloxygenase-2 inhibition augments the efficacy of a cancer vaccine. Clin.Cancer Res. 12: 214-222.
57. Hahn, T., Alvarez, I., Kobie, J.J., Ramanathapuram, L., Dial, S., Fulton, A., Besselsen, D.,Walker, E., Akporiaye, E.T. (2006). Short-term dietary administration of celecoxibenhances the efficacy of tumor lysate-pulsed dendritic cell vaccines in treatingmurine breast cancer. Inter. J. Cancer 118: 2220-2231.
58. Harris, A.L. (2002). Hypoxia-a key regulatory factor in tumour growth. Nature Rev.Cancer 2: 38-47.
59. Hendricks, A., Leibold, W., Kaever, V., Schuberth, H.J. (2000). Prostaglandin E2 isvariably induced by bacterial superantigens in bovine mononuclear cells and has aregulatory role for the T cell proliferative response. Immunobiology 201: 493-505.
60. Hoechst, B., Ormandy, L.A., Ballmaier, M., Lehner, F., Kruger, C., Manns, M.P., Greten,T.F., Korangy, F. (2008). A new population of myeloid-derived suppressor cells inhepatocellular carcinoma patients induces CD4( +)CD25( +)Foxp3( +) T cells.Gastroenterology 135: 234-243.
61. Hoechst, B., Voigtlaender, T., Ormandy, L., Gamrekelashvili, J., Zhao, F., Wedemeyer,H., Lehner, F., Manns, M.P., Greten, T.F., Korangy, F. (2009). Myeloid derivedsuppressor cells inhibit natural killer cells in patients with hepatocellular carcinomavia the NKp30 receptor. Hepatology 50: 799-807.
62. Holt, D., Ma, X., Kundu, N., Fulton, A. (2011). Prostaglandin E(2) (PGE (2)) suppressesnatural killer cell function primarily through the PGE(2) receptor EP4. CancerImmunol. Immunother. 60: 1577-15866
63. Honda, A., Sugimoto, Y., Namba, T., Watabe, A., Irie, A., Negishi, M., Narumiya, S.,Ichikawa, A. (1993). Cloning and expression of a cDNA for mouse prostaglandin Ereceptor EP2 subtype. J. Biol. Chem. 268: 7759-7762.
64. Huang, B., Pan, P.Y., Li, Q., Sato, A.I., Levy, D.E., Bromberg, J., Divino, C.M., Chen, S.H.(2006). Gr-1 +CD115 + immature myeloid suppressor cells mediate the developmentof tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. CancerRes. 66: 1123-1131.
65. Hwu, P., Du, M.X., Lapointe, R., Do, M., Taylor, M.W., Young, H.A. (2000). Indoleamine2,3-dioxygenase production by human dendritic cells results in the inhibition of T cellproliferation. J. Immunol. 164: 3596-3599.
66. Jung, Y.J., Isaacs, J.S., Lee, S., Trepel, J., Neckers, L. (2003). IL-1beta-mediatedup-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1as a critical link between inflammation and oncogenesis. FASEB J. 17: 2115-2117.
67. Kalinski, P. (2012). Regulation of immune responses by prostaglandin E2. J. Immunol.188: 21-28.
68. Kalinski, P., Hilkens, C.M., Snijders, A., Snijdewint, F.G., Kapsenberg, M.L. (1997). IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promotetype 2 cytokine production in maturing human naive T helper cells. J. Immunol.159: 28-35.
69. Kalinski, P., Hilkens, C.M., Wierenga, E.A., Kapsenberg, M.L. (1999). T-cell priming bytype-1 and type-2 polarized dendritic cells: the concept of a third signal. Immunol.Today 20: 561-567.
70. Kalinski, P., Schuitemaker, J.H., Hilkens, C.M., Kapsenberg, M.L. (1998). ProstaglandinE2 induces the final maturation of IL-12-deficient CD1a +CD83 + dendritic cells: thelevels of IL-12 are determined during the final dendritic cell maturation and areresistant to further modulation. J. Immunol. 161: 2804-2809.
71. Kanayama, S., Yamada, Y., Kawaguchi, R., Tsuji, Y., Haruta, S., Kobayashi, H. (2008).Hepatocyte growth factor induces anoikis resistance by up-regulation ofcyclooxygenase-2 expression in uterine endometrial cancer cells. Oncol. Rep.19: 117-122.
72. Katz, J.B., Muller, A.J., Prendergast, G.C. (2008). Indoleamine 2,3-dioxygenase in T-celltolerance and tumoral immune escape. Immunol. Rev. 222: 206-221.
73. Kortylewski, M., Kujawski, M., Wang, T., Wei, S., Zhang, S., Pilon-Thomas, S., Niu, G.,Kay, H., Mule, J., Kerr, W.G., et al. (2005). Inhibiting Stat3 signaling in the hematopoieticsystem elicits multicomponent antitumor immunity. Nat. Med. 11: 1314-1321.
74. Kusmartsev, S., Gabrilovich, D.I. (2003). Inhibition of myeloid cell differentiation incancer: the role of reactive oxygen species. J. Leukocyte Biol. 74: 186-196.
75. Kusmartsev, S., Gabrilovich, D.I. (2005). STAT1 signaling regulates tumor-associatedmacrophage-mediated T cell deletion. J. Immunol. 174: 4880-4891.
76. Kusmartsev, S., Nagaraj, S., Gabrilovich, D.I. (2005). Tumor-associated CD8 + T celltolerance induced by bone marrow-derived immature myeloid cells. J. Immunol.175: 4583-4592.
77. Lee, S.Y., Choi, H.K., Lee, K.J., Jung, J.Y., Hur, G.Y., Jung, K.H., Kim, J.H., Shin, C.,Shim, J.J. In, K.H., et al. (2009). The immune tolerance of cancer is mediated by IDOthat is inhibited by COX-2 inhibitors through regulatory T cells. J. Immunother.32: 22-28.
78. Li, H., Han, Y., Guo, Q., Zhang, M., Cao, X. (2009). Cancer-expanded myeloid-derivedsuppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1.J. Immunol. 182: 240-249.
79. Linnemeyer, P.A., and Pollack, S.B. (1993). Prostaglandin E2-induced changes in thephenotype, morphology, and lytic activity of IL-2-activated natural killer cells.J. Immunol. 150: 3747-3754.
80. Liu, Y., Zeng, B., Zhang, Z., Zhang, Y., Yang, R. (2008). B7-H1 on myeloid-derivedsuppressor cells in immune suppression by a mouse model of ovarian cancer. Clin.Immunol. 129: 471-481.
81. Mannick, J.B., Hausladen, A., Liu, L., Hess, D.T., Zeng, M., Miao, Q.X., Kane, L.S., Gow,A.J., Stamler, J.S. (1999). Fas-induced caspase denitrosylation. Science 284: 651-654.
82. Mazzoni, A., Bronte, V., Visintin, A., Spitzer, J.H., Apolloni, E., Serafini, P., Zanovello, P.,Segal, D.M. (2002). Myeloid suppressor lines inhibit T cell responses by an NOdependentmechanism. J. Immunol. 168: 689-695.
83. Mellor, A.L., Munn, D.H. (2004). IDO expression by dendritic cells: tolerance and tryptophancatabolism. Nat. Rev. Immunol. 4: 762-774.
84. 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( +) progenitorsby tumor cells: role of interleukin-6 and macrophage colony-stimulating factor.Blood 92: 4778-4791.
85. Moore, A.E., Greenhough, A., Roberts, H.R., Hicks, D.J., Patsos, H.A., Williams, A.C.,Paraskeva, C. (2009). HGF/Met signalling promotes PGE(2) biogenesis via regulationof COX-2 and 15-PGDH expression in colorectal cancer cells. Carcinogenesis30: 1796-1804.
86. 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 discretetumor-induced myeloid-derived suppressor cell subpopulations with distinct Tcell-suppressive activity. Blood 111: 4233-4244.
87. Mukherjee, P., Basu, G.D., Tinder, T.L., Subramani, D.B., Bradley, J.M., Arefayene, M.,Skaar, T., De Petris, G. (2009). Progression of pancreatic adenocarcinoma is significantlyimpeded with a combination of vaccine and COX-2 inhibition. J. Immunol.182: 216-224.
88. Muller, A.J., Scherle, P.A. (2006). Targeting the mechanisms of tumoral immune tolerancewith small-molecule inhibitors. Nat. Rev. Cancer 6: 613-625.
89. Mundy-Bosse, B.L., Young, G.S., Bauer, T., Binkley, E., Bloomston, M., Bill, M.A., Bekaii-Saab, T., Carson, W.E., 3rd, Lesinski, G.B. (2011). Distinct myeloid suppressor cellsubsets correlate with plasma IL-6 and IL-10 and reduced interferon-alpha signalingin CD4( +) T cells from patients with GI malignancy. Cancer Immunol Immunother.2011; 60(9): 1269-1279.
90. Munn, D.H., Mellor, A.L. (2007). Indoleamine 2,3-dioxygenase and tumor-induced tolerance.J. Clin. Invest. 117: 1147-1154.
91. Munn, D.H., Shafizadeh, E., Attwood, J.T., Bondarev, I., Pashine, A., Mellor, A.L. (1999).Inhibition of T cell proliferation by macrophage tryptophan catabolism. J. Exp. Med.189: 1363-1372.
92. Murdoch, C., Muthana, M., Coffelt, S.B., Lewis, C.E. (2008). The role of myeloid cells inthe promotion of tumour angiogenesis. Nat. Rev. Cancer 8: 618-631.
93. Naito, Y., Endo, H., Arai, K., Coffman, R.L., Arai, N. (1996). Signal transduction in Thclones: target of differential modulation by PGE2 may reside downstream of thePKC-dependent pathway. Cytokine 8: 346-356.
94. Nefedova, Y., Huang, M., Kusmartsev, S., Bhattacharya, R., Cheng, P., Salup, R., Jove,R., Gabrilovich, D. (2004). Hyperactivation of STAT3 is involved in abnormal differentiationof dendritic cells in cancer. J. Immunol. 172: 464-474.
95. Nefedova, Y., Nagaraj, S., Rosenbauer, A., Muro-Cacho, C., Sebti, S.M., Gabrilovich, D.I.(2005). Regulation of dendritic cell differentiation and antitumor immune responsein cancer by pharmacologic-selective inhibition of the janus-activated kinase 2/signaltransducers and activators of transcription 3 pathway. Cancer Res. 65: 9525-9535.
96. Obermajer, N., Muthuswamy, R., Lesnock, J., Edwards, R.P., Kalinski, P. (2011a).Positive feedback between PGE2 and COX2 redirects the differentiation of humandendritic cells toward stable myeloid-derived suppressor cells. Blood 118: 5498-5505.
97. Obermajer, N., Muthuswamy, R., Odunsi, K., Edwards, R.P., Kalinski, P. (2011b). PGE2-induced CXCL12 production and CXCR4 expression controls the accumulation ofhuman MDSCs in ovarian cancer environment. Cancer Res. 71: 7463-7470.
98. Ochoa, A.C., Zea, A.H., Hernandez, C., Rodriguez, P.C. (2007). Arginase, prostaglandins,and myeloid-derived suppressor cells in renal cell carcinoma. Clin. Cancer Res.13: 721s-726s.
99. Orabona, C., Pallotta, M.T., Volpi, C., Fallarino, F., Vacca, C., Bianchi, R., Belladonna,M.L., Fioretti, M.C., Grohmann, U., Puccetti, P. (2008). SOCS3 drives proteasomaldegradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependenttolerogenesis. Proc. Natl. Acad. Sci. USA 105: 20828-20833.
100. Ostrand-Rosenberg, S. (2010). Myeloid-derived suppressor cells: more mechanisms forinhibiting antitumor immunity. Cancer Immunol. Immunother. 59: 1593-1600.
101. Ozaki, Y., Edelstein, M.P., Duch, D.S. (1988). Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma. Proc. Natl. Acad. Sci.USA 85: 1242-1246.
102. Pan, P.Y., Ma, G., Weber, K.J., Ozao-Choy, J., Wang, G., Yin, B., Divino, C.M., Chen, S.H.(2010). Immune stimulatory receptor CD40 is required for T-cell suppression and Tregulatory cell activation mediated by myeloid-derived suppressor cells in cancer.Cancer Res. 70: 99-108.
103. Pan, P.Y., Wang, G.X., Yin, B., Ozao, J., Ku, T., Divino, C.M., Chen, S.H. (2008).Reversion of immune tolerance in advanced malignancy: modulation of myeloidderivedsuppressor cell development by blockade of stem-cell factor function. Blood111: 219-228.
104. Parhar, R.S., Lala, P.K. (1988). Prostaglandin E2-mediated inactivation of various killerlineage cells by tumor-bearing host macrophages. J. Leukocyte Biol. 44: 474-484.
105. Peranzoni, E., Zilio, S., Marigo, I., Dolcetti, L., Zanovello, P., Mandruzzato, S., Bronte, V.(2010). Myeloid-derived suppressor cell heterogeneity and subset definition. Curr.Opin. Immunol. 22: 238-244.
106. Prendergast, G.C. (2008). Immune escape as a fundamental trait of cancer: focus on IDO.Oncogene 27: 3889-3900.
107. Prendergast, G.C., Metz, R., Muller, A.J. (2010). Towards a genetic definition of cancerassociatedinflammation: role of the IDO pathway. Amer. J. Pathol. 176: 2082-2087.
108. Raychaudhuri, B., Rayman, P., Ireland, J., Ko, J., Rini, B., Borden, E.C., Garcia, J.,Vogelbaum, M.A., Finke, J. (2011). Myeloid-derived suppressor cell accumulation andfunction in patients with newly diagnosed glioblastoma. Neuro. Oncol. 13: 591-599.
109. Regan, J.W., Bailey, T.J., Pepperl, D.J., Pierce, K.L., Bogardus, A.M., Donello, J.E.,Fairbairn, C.E., Kedzie, K.M., Woodward, D.F., Gil, D.W. (1994). Cloning of a novelhuman prostaglandin receptor with characteristics of the pharmacologically definedEP2 subtype. Mol. Pharmacol. 46: 213-220.
110. Rodriguez, P.C., Ernstoff, M.S., Hernandez, C., Atkins, M., Zabaleta, J., Sierra, R., Ochoa,A.C. (2009). Arginase I-producing myeloid-derived suppressor cells in renal cellcarcinoma are a subpopulation of activated granulocytes. Cancer Res. 69: 1553-1560.
111. 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 byCOX-2 in lung carcinoma. J. Exp. Med. 202: 931-939.
112. Rodriguez, P.C., Ochoa, A.C. (2008). Arginine regulation by myeloid derived suppressorcells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol.Rev. 222: 180-191.
113. Rodriguez, P.C., Quiceno, D.G., Zabaleta, J., Ortiz, B., Zea, A.H., Piazuelo, M.B., Delgado,A., Correa, P., Brayer, J., Sotomayor, E.M., et al. (2004). Arginase I production in thetumor microenvironment by mature myeloid cells inhibits T-cell receptor expressionand antigen-specific T-cell responses. Cancer Res. 64: 5839-5849.
114. Rodriguez, P.C., Zea, A.H., DeSalvo, J., Culotta, K.S., Zabaleta, J., Quiceno, D.G.,Ochoa, J.B., Ochoa, A.C. (2003). L-arginine consumption by macrophages modulatesthe expression of CD3 zeta chain in T lymphocytes. J. Immunol. 171: 1232-1239.
115. Rutella, S., Bonanno, G., Procoli, A., Mariotti, A., de Ritis, D.G., Curti, A., Danese, S.,Pessina, G., Pandolfi, S., Natoni, F., et al. (2006). Hepatocyte growth factor favorsmonocyte differentiation into regulatory interleukin (IL)-10 + +IL-12low/neg accessorycells with dendritic-cell features. Blood 108: 218-227.
116. Scarpino, S., Duranti, E., Stoppacciaro, A., Pilozzi, E., Natoli, G., Sciacchitano, S.,Luciani, E., Ruco, L. (2009). COX-2 is induced by HGF stimulation in Met-positivethyroid papillary carcinoma cells and is involved in tumour invasiveness. J. Pathol.218: 487-494.
117. Schmedtje, J.F., Jr., Ji, Y.S., Liu, W.L., DuBois, R.N., Runge, M.S. (1997). Hypoxiainduces cyclooxygenase-2 via the NF-kappaB p65 transcription factor in humanvascular endothelial cells. J. Biol. Chem. 272: 601-608.
118. Schmielau, J., Finn, O.J. (2001). Activated granulocytes and granulocyte-derived hydrogenperoxide are the underlying mechanism of suppression of t-cell function inadvanced cancer patients. Cancer Res. 61: 4756-4760.
119. Schwacha, M.G., Ayala, A., Cioffi, W.G., Bland, K.I., Chaudry, I.H. (1999). Role of proteinkinase C in cyclic AMP-mediated suppression of T-lymphocyte activation followingburn injury. Biochim. Biophys. Acta 1455: 45-53.
120. Semenza, G.L. (2003). Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3: 721-732.
121. Serafini, P. (2010). Editorial: PGE2-producing MDSC: a role in tumor progression?J. Leukocyte Biol. 88: 827-829.
122. Serafini, P., Meckel, K., Kelso, M., Noonan, K., Califano, J., Koch, W., Dolcetti, L., Bronte,V., Borrello, I. (2006). Phosphodiesterase-5 inhibition augments endogenous antitumorimmunity by reducing myeloid-derived suppressor cell function. J. Exp. Med.203: 2691-2702.
123. Serafini, P., Mgebroff, S., Noonan, K., Borrello, I. (2008). Myeloid-derived suppressorcells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells.Cancer Res. 68: 5439-5449.
124. Sharma, M.D., Baban, B., Chandler, P., Hou, D.Y., Singh, N., Yagita, H., Azuma, M.,Blazar, B.R., Mellor, A.L., Munn, D.H. (2007). Plasmacytoid dendritic cells frommouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine2,3-dioxygenase. J. Clin. Invest. 117: 2570-2582.
125. Sharma, S., Yang, S.C., Zhu, L., Reckamp, K., Gardner, B., Baratelli, F., Huang, M.,Batra, R.K., Dubinett, S.M. (2005a). Tumor cyclooxygenase-2/ prostaglandin E2-dependent promotion of FOXP3 expression and CD4 + CD25 + T regulatory cellactivities in lung cancer. Cancer Res. 65: 5211-5220.
126. Sharma, S., Zhu, L., Yang, S.C., Zhang, L., Lin, J., Hillinger, S., Gardner, B., Reckamp, K.,Strieter, R.M., Huang, M., et al. (2005b). Cyclooxygenase 2 inhibition promotes IFNgamma-dependent enhancement of antitumor responses. J. Immunol. 175: 813-819.
127. Siegfried, J.M., Gubish, C.T., Rothstein, M.E., Queiroz de Oliveira, P.E., Stabile, L.P.(2007). Signaling pathways involved in cyclooxygenase-2 induction by hepatocytegrowth factor in non small-cell lung cancer. Mol. Pharmacol. 72: 769-779.
128. Sinha, P., Clements, V.K., Bunt, S.K., Albelda, S.M., Ostrand-Rosenberg, S. (2007a).Cross-talk between myeloid-derived suppressor cells and macrophages subvertstumor immunity toward a type 2 response. J. Immunol. 179: 977-983.
129. Sinha, P., Clements, V.K., Fulton, A.M., Ostrand-Rosenberg, S. (2007b). ProstaglandinE2 promotes tumor progression by inducing myeloid-derived suppressor cells.Cancer Res. 67: 4507-4513.
130. Sinha, P., Clements, V.K., Ostrand-Rosenberg, S. (2005). Reduction of myeloid-derivedsuppressor cells and induction of M1 macrophages facilitate the rejection of establishedmetastatic disease. J. Immunol. 174: 636-645.
131. Specht, C., Bexten, S., Kolsch, E., Pauels, H.G. (2001). Prostaglandins, but not tumorderivedIL-10, shut down concomitant tumor-specific CTL responses during murineplasmacytoma progression. Inter. J. Cancer 91: 705-712.
132. Stolina, M., Sharma, S., Lin, Y., Dohadwala, M., Gardner, B., Luo, J., Zhu, L.,Kronenberg, M., Miller, P.W., Portanova, J., et al. (2000). Specific inhibition ofcyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 andIL-12 synthesis. J. Immunol. 164: 361-370.
133. Su, Y., Jackson, E.K., Gorelik, E. (2011). Receptor desensitization and blockade of thesuppressive effects of prostaglandin E(2) and adenosine on the cytotoxic activity ofhuman melanoma-infiltrating T lymphocytes. Cancer Immunol. Immunother.60: 111-122.
134. Subbaramaiah, K., Dannenberg, A.J. (2003). Cyclooxygenase 2: a molecular target forcancer prevention and treatment. Trends Pharmacol. Sci. 24: 96-102.
135. Tai, H.H., Ensor, C.M., Tong, M., Zhou, H., Yan, F. (2002). Prostaglandin catabolizingenzymes. Prostaglandins Lipid Mediat. 68-69: 483-493.
136. Talmadge, J.E., Hood, K.C., Zobel, L.C., Shafer, L.R., Coles, M., Toth, B. (2007).Chemoprevention by cyclooxygenase-2 inhibition reduces immature myeloid suppressorcell expansion. Int. Immunopharmacol. 7: 140-151.
137. Timoshenko, A.V., Lala, P.K., Chakraborty, C. (2004). PGE2-mediated upregulation ofiNOS in murine breast cancer cells through the activation of EP4 receptors. Inter.J. Cancer 108: 384-389.
138. Uyttenhove, C., Pilotte, L., Theate, I., Stroobant, V., Colau, D., Parmentier, N., Boon, T.,Van den Eynde, B.J. (2003). Evidence for a tumoral immune resistance mechanismbased on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med.9: 1269-1274.
139. Van Ginderachter, J.A., Meerschaut, S., Liu, Y., Brys, L., De Groeve, K., HassanzadehGhassabeh, G., Raes, G., De Baetselier, P. (2006). Peroxisome proliferator-activatedreceptor gamma (PPARgamma) ligands reverse CTL suppression by alternativelyactivated (M2) macrophages in cancer. Blood 108: 525-535.
140. Vang, T., Abrahamsen, H., Myklebust, S., Horejsi, V., Tasken, K. (2003). Combinedspatial and enzymatic regulation of Csk by cAMP and protein kinase a inhibitsT cell receptor signaling. J. Biol. Chem. 278: 17597-17600.
141. 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 isassociated with decreased numbers of myeloid-derived suppressor cells in mesothelioma.Celecoxib influences MDSC function. BMC Cancer 10: 464.
142. von Bergwelt-Baildon, M.S., Popov, A., Saric, T., Chemnitz, J., Classen, S., Stoffel, M.S.,Fiore, F., Roth, U., Beyer, M., Debey, S., et al. (2006). CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associateddendritic cells in vivo: additional mechanisms of T-cell inhibition. Blood 108: 228-237.
143. Vuk-Pavlovic, S., Bulur, P.A., Lin, Y., Qin, R., Szumlanski, C.L., Zhao, X., Dietz, A.B.Immunosuppressive CD14 +HLA-DRlow/-monocytes in prostate cancer. Prostate70: 443-455.
144. Wu, C.Y., Wang, K., McDyer, J.F., Seder, R.A. (1998). Prostaglandin E2 and dexamethasoneinhibit IL-12 receptor expression and IL-12 responsiveness. J. Immunol.161: 2723-2730.
145. Xia, Y., Roman, L.J., Masters, B.S., Zweier, J.L. (1998). Inducible nitric-oxide synthasegenerates superoxide from the reductase domain. J. Biol. Chem. 273: 22635-22639.
146. Xia, Y., Zweier, J.L. (1997). Superoxide and peroxynitrite generation from inducible nitricoxide synthase in macrophages. Proc. Natl. Acad. Sci. USA 94: 6954-6958.
147. Xu, H., Oriss, T.B., Fei, M., Henry, A.C., Melgert, B.N., Chen, L., Mellor, A.L., Munn,D.H., Irvin, C.G., Ray, P., et al. (2008a). Indoleamine 2,3-dioxygenase in lung dendriticcells promotes Th2 responses and allergic inflammation. Proc. Natl. Acad. Sci.USA 105: 6690-6695.
148. Xu, H., Zhang, G.X., Ciric, B., Rostami, A. (2008b). IDO: a double-edged sword for T(H)1/T(H)2 regulation. Immunol. Lett. 121: 1-6.
149. Yakar, I., Melamed, R., Shakhar, G., Shakhar, K., Rosenne, E., Abudarham, N., Page,G.G., and Ben-Eliyahu, S. (2003). Prostaglandin e(2) suppresses NK activity in vivoand promotes postoperative tumor metastasis in rats. Ann. Surg. Oncol. 10: 469-479.
150. Yang, L., DeBusk, L.M., Fukuda, K., Fingleton, B., Green-Jarvis, B., Shyr, Y., Matrisian,L.M., Carbone, D.P., Lin, P.C. (2004). Expansion of myeloid immune suppressorGr +CD11b + cells in tumor-bearing host directly promotes tumor angiogenesis.Cancer Cell 6: 409-421.
151. Yang, R., Cai, Z., Zhang, Y., Yutzy, W.H.t., Roby, K.F., Roden, R.B. (2006). CD80 inimmune suppression by mouse ovarian carcinoma-associated Gr-1 +CD11b + myeloidcells. Cancer Res. 66: 6807-6815.
152. Youn, J.I., Nagaraj, S., Collazo, M., Gabrilovich, D.I. (2008). Subsets of myeloid-derivedsuppressor cells in tumor-bearing mice. J. Immunol. 181: 5791-5802.
153. Young, M.R., Wright, M.A. (1992). Myelopoiesis-associated immune suppressor cells inmice bearing metastatic Lewis lung carcinoma tumors: gamma interferon plustumor necrosis factor alpha synergistically reduces immune suppressor and tumorgrowth-promoting activities of bone marrow cells and diminishes tumor recurrenceand metastasis. Cancer Res. 52: 6335-6340.