Myeloid-derived suppressor cells as regulators of the immune system (original) (raw)

• Young, M. R. I., Newby, M. & Wepsic, T. H. Hematopoiesis and suppressor bone marrow cells in mice bearing large metastatic Lewis lung carcinoma tumors. Cancer Res. 47, 100–106 (1987).
  CAS PubMed Google Scholar
• Buessow, S. C., Paul, R. D. & Lopez, D. M. Influence of mammary tumor progression on phenotype and function of spleen and in situ lymphocytes in mice. J. Natl Cancer Inst. 73, 249–255 (1984).
  CAS PubMed Google Scholar
• Seung, L., Rowley, D., Dubeym, P. & Schreiber, H. Synergy between T-cell immunity and inhibition of paracrine stimulation causes tumor rejection. Proc. Natl Acad. Sci. USA 92, 6254–6258 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Sinha, P., Clements, V. K., Bunt, S. K., Albelda, S. M. & Ostrand-Rosenberg, S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J. Immunol. 179, 977–983 (2007).
  Article CAS PubMed Google Scholar
• Murdoch, C., Muthana, M., Coffelt, S. B. & Lewis, C. E. The role of myeloid cells in the promotion of tumour angiogenesis. Nature Rev. Cancer 8, 618–631 (2008).
  Article CAS Google Scholar
• Youn, J. I., Nagaraj, S., Collazo, M. & Gabrilovich, D. I. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J. Immunol. 181, 5791–5802 (2008).
  Article CAS PubMed Google Scholar
• Bronte, V. et al. Identification of a CD11b+/Gr-1+/CD31+ myeloid progenitor capable of activating or suppressing CD8+ T cells. Blood 96, 3838–3846 (2000).
  CAS PubMed Google Scholar
• Kusmartsev, S. & Gabrilovich, D. I. Inhibition of myeloid cell differentiation in cancer: The role of reactive oxygen species. J. Leukoc. Biol. 74, 186–196 (2003).
  Article CAS PubMed Google Scholar
• Li, Q., Pan, P. Y., Gu, P., Xu, D. & Chen, S. H. Role of immature myeloid Gr-1+ cells in the development of antitumor immunity. Cancer Res. 64, 1130–1139 (2004).
  Article CAS PubMed Google Scholar
• Kusmartsev, S., Nefedova, Y., Yoder, D. & Gabrilovich, D. I. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J. Immunol. 172, 989–999 (2004).
  Article CAS PubMed Google Scholar
• Ochoa, A. C., Zea, A. H., Hernandez, C. & Rodriguez, P. C. Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin. Cancer Res. 13, 721s–726s (2007).
  Article CAS PubMed Google Scholar
• Almand, B. et al. Increased production of immature myeloid cells in cancer patients. A mechanism of immunosuppression in cancer. J. Immunol. 166, 678–689 (2001).
  Article CAS PubMed Google Scholar
• Schmielau, J. & Finn, O. J. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of T-cell function in advanced cancer patients. Cancer Res. 61, 4756–4760 (2001).
  CAS PubMed Google Scholar
• Hestdal, K. et al. Characterization and regulation of RB6–8C5 antigen expression on murine bone marrow cells. J. Immunol. 147, 22–28 (1991).
  CAS PubMed Google Scholar
• Dietlin, T. A. et al. Mycobacteria-induced Gr-1+ subsets from distinct myeloid lineages have opposite effects on T cell expansion. J. Leukoc. Biol. 81, 1205–1212 (2007).
  Article CAS PubMed Google Scholar
• Zhu, B. et al. CD11b+Ly-6Chi suppressive monocytes in experimental autoimmune encephalomyelitis. J. Immunol. 179, 5228–5237 (2007).
  Article CAS PubMed Google Scholar
• Movahedi, K. et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T-cell suppressive activity. Blood 111, 4233–4244 (2008). Together with reference 6, this paper describes functional differences between subsets of MDSCs.
  Article CAS PubMed Google Scholar
• Yang, R. et al. CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1+CD11b+ myeloid cells. Cancer Res. 66, 6807–6815 (2006).
  Article CAS PubMed Google Scholar
• Huang, B. et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res. 66, 1123–1131 (2006).
  Article CAS PubMed Google Scholar
• Gallina, G. et al. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J. Clin. Invest. 116, 2777–2790 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Mirza, N. et al. All-_trans_-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res. 66, 9299–9307 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Diaz-Montero, C. M. et al. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin–cyclophosphamide chemotherapy. Cancer Immunol. Immunother. 58, 49–59 (2009).
  Article CAS PubMed Google Scholar
• Goni, O., Alcaide, P. & Fresno, M. Immunosuppression during acute Trypanosoma cruzi infection: involvement of Ly6G (Gr1+)CD11b+ immature myeloid suppressor cells. Int. Immunol. 14, 1125–1134 (2002).
  Article CAS PubMed Google Scholar
• Giordanengo, L. et al. Cruzipain, a major Trypanosoma cruzi antigen, conditions the host immune response in favor of parasite. Eur. J. Immunol. 32, 1003–1011 (2002).
  Article CAS PubMed Google Scholar
• Voisin, M. B., Buzoni-Gatel, D., Bout, D. & Velge-Roussel, F. Both expansion of regulatory GR1+ CD11b+ myeloid cells and anergy of T lymphocytes participate in hyporesponsiveness of the lung-associated immune system during acute toxoplasmosis. Infect. Immun. 72, 5487–5492 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Delano, M. J. et al. MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis. J. Exp. Med. 204, 1463–1474 (2007). This is the first demonstration of a direct role for TLR signalling in the expansion of MDSCs.
  Article CAS PubMed PubMed Central Google Scholar
• Sunderkotter, C. et al. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J. Immunol. 172, 4410–4417 (2004).
  Article PubMed Google Scholar
• Terrazas, L. I., Walsh, K. L., Piskorska, D., McGuire, E. & Harn, D. A. Jr. The schistosome oligosaccharide lacto-_N_-neotetraose expands Gr1+ cells that secrete anti-inflammatory cytokines and inhibit proliferation of naive CD4+ cells: a potential mechanism for immune polarization in helminth infections. J. Immunol. 167, 5294–5303 (2001).
  Article CAS PubMed Google Scholar
• Gomez-Garcia, L. et al. Intact glycans from cestode antigens are involved in innate activation of myeloid suppressor cells. Parasite Immunol. 27, 395–405 (2005).
  Article CAS PubMed Google Scholar
• Brys, L. et al. Reactive oxygen species and 12/15-lipoxygenase contribute to the antiproliferative capacity of alternatively activated myeloid cells elicited during helminth infection. J. Immunol. 174, 6095–6104 (2005).
  Article CAS PubMed Google Scholar
• Mencacci, A. et al. CD80+Gr-1+ myeloid cells inhibit development of antifungal Th1 immunity in mice with candidiasis. J. Immunol. 169, 3180–3190 (2002).
  Article CAS PubMed Google Scholar
• Ezernitchi, A. V. et al. TCR ζ down-regulation under chronic inflammation is mediated by myeloid suppressor cells differentially distributed between various lymphatic organs. J. Immunol. 177, 4763–4772 (2006).
  Article CAS PubMed Google Scholar
• Kerr, E. C., Raveney, B. J., Copland, D. A., Dick, A. D. & Nicholson, L. B. Analysis of retinal cellular infiltrate in experimental autoimmune uveoretinitis reveals multiple regulatory cell populations. J. Autoimmun. 31, 354–361 (2008).
  Article CAS PubMed Google Scholar
• Marhaba, R. et al. The importance of myeloid-derived suppressor cells in the regulation of autoimmune effector cells by a chronic contact eczema. J. Immunol. 179, 5071–5081 (2007).
  Article CAS PubMed Google Scholar
• Haile, L. A. et al. Myeloid-derived suppressor cells in inflammatory bowel disease: a new immunoregulatory pathway. Gastroenterology 135, 871–881 (2008).
  Article CAS PubMed Google Scholar
• Makarenkova, V. P., Bansal, V., Matta, B. M., Perez, L. A. & Ochoa, J. B. CD11b+/Gr-1+ myeloid suppressor cells cause T cell dysfunction after traumatic stress. J. Immunol. 176, 2085–2094 (2006).
  Article CAS PubMed Google Scholar
• Bronte, V. et al. Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells. J. Immunol. 161, 5313–5320 (1998).
  CAS PubMed Google Scholar
• Cauley, L., Miller, E., Yen, M. & Swain, S. Superantigen-induced CD4 T cell tolerance mediated by myeloid cells and IFN-γ. J. Immunol. 165, 6056–6066 (2000).
  Article CAS PubMed Google Scholar
• Pan, P. Y. et al. Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function. Blood 111, 219–228 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Sinha, P., Clements, V. K., Fulton, A. M. & Ostrand-Rosenberg, S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. 67, 4507–4513 (2007).
  Article CAS PubMed Google Scholar
• Serafini, P. et al. High-dose GM-CSF-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer Res. 64, 6337–6343 (2004).
  Article CAS PubMed Google Scholar
• Bunt, S. K. et al. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res. 67, 10019–10026 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Gabrilovich, D. et al. 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 (1998).
  CAS PubMed Google Scholar
• Bromberg, J. Stat proteins and oncogenesis. J. Clin. Invest. 109, 1139–1142 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Nefedova, Y. et al. 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 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Nefedova, Y. et al. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J. Immunol. 172, 464–474 (2004).
  Article CAS PubMed Google Scholar
• Kortylewski, M. et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nature Med. 11, 1314–1321 (2005).
  Article CAS PubMed Google Scholar
• Foell, D., Wittkowski, H., Vogl, T. & Roth, J. S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J. Leukoc. Biol. 81, 28–37 (2007).
  Article CAS PubMed Google Scholar
• Cheng, P. et al. 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 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Sinha, P. et al. Proinflammatory s100 proteins regulate the accumulation of myeloid-derived suppressor cells. J. Immunol. 181, 4666–4675 (2008). References 49 and 50 describe a new role for S100 proteins in the regulation of MDSC expansion in cancer.
  Article CAS PubMed Google Scholar
• Turovskaya, O. et al. RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis. Carcinogenesis 29, 2035–2043 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Kusmartsev, S. & Gabrilovich, D.I. STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J. Immunol. 174, 4880–4891 (2005).
  Article CAS PubMed Google Scholar
• Kusmartsev, S., Nagaraj, S. & Gabrilovich, D. I. Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J. Immunol. 175, 4583–4592 (2005).
  Article CAS PubMed Google Scholar
• Bronte, V. et al. IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J. Immunol. 170, 270–278 (2003).
  Article CAS PubMed Google Scholar
• Rutschman, R. et al. Cutting Edge: Stat6-dependent substrate depletion regulates nitric oxide production. J. Immunol. 166, 2173–2177 (2001).
  Article CAS PubMed Google Scholar
• Sinha, P., Clements, V. K. & Ostrand-Rosenberg, S. Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis. Cancer Res. 65, 11743–11751 (2005).
  Article CAS PubMed Google Scholar
• Terabe, M. et al. Transforming growth factor-β production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J. Exp. Med. 198, 1741–1752 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Serafini, P., Mgebroff, S., Noonan, K. & Borrello, I. Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res. 68, 5439–5449 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Bronte, V. & Zanovello, P. Regulation of immune responses by L-arginine metabolism. Nature Rev. Immunol. 5, 641–654 (2005).
  Article CAS Google Scholar
• Rodriguez, P. C. & Ochoa, A. C. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol. Rev. 222, 180–191 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Rodriguez, P. C. et al. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J. Exp. Med. 202, 931–939 (2005). This study shows that prostaglandin E2 has an important role in MDSC-mediated T-2011 cell suppression and suggests a new therapeutic target for the treatment of cancer.
  Article CAS PubMed PubMed Central Google Scholar
• Rodriguez, P. C. et al. Regulation of T cell receptor CD3ζ chain expression by L-arginine. J. Biol. Chem. 277, 21123–21129 (2002).
  Article CAS PubMed Google Scholar
• Rodriguez, P. C., Quiceno, D. G. & Ochoa, A. C. L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109, 1568–1573 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Bingisser, R., Tilbrook, P., Holt, P. & Kees, U. Macrophage-derived nitric oxide regulates T-cell activation via reversible disruption of the Jak3/STAT5 signaling pathway. J. Immunol. 160, 5729–5734 (1998).
  CAS PubMed Google Scholar
• Harari, O. & Liao, J. K. Inhibition of MHC II gene transcription by nitric oxide and antioxidants. Curr. Pharm. Des. 10, 893–898 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Rivoltini, L. et al. Immunity to cancer: attack and escape in T lymphocyte–tumor cell interaction. Immunol. Rev. 188, 97–113 (2002).
  Article CAS PubMed Google Scholar
• Szuster-Ciesielska, A., Hryciuk-Umer, E., Stepulak, A., Kupisz, K. & Kandefer-Szerszen, M. Reactive oxygen species production by blood neutrophils of patients with laryngeal carcinoma and antioxidative enzyme activity in their blood. Acta Oncol. 43, 252–258 (2004).
  Article CAS PubMed Google Scholar
• Waris, G. & Ahsan, H. Reactive oxygen species: role in the development of cancer and various chronic conditions. J. Carcinog. 5, 14 (2006).
  Article PubMed PubMed Central CAS Google Scholar
• Mantovani, G. et al. Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress. J. Mol. Med. 81, 664–673 (2003).
  Article CAS PubMed Google Scholar
• Agostinelli, E. & Seiler, N. Non-irradiation-derived reactive oxygen species (ROS) and cancer: therapeutic implications. Amino Acids 31, 341–355 (2006).
  Article CAS PubMed Google Scholar
• Sauer, H., Wartenberg, M. & Hescheler, J. Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell. Physiol. Biochem. 11, 173–186 (2001).
  Article CAS PubMed Google Scholar
• Vickers, S. M., MacMillan-Crow, L. A., Green, M., Ellis, C. & Thompson, J. A. Association of increased immunostaining for inducible nitric oxide synthase and nitrotyrosine with fibroblast growth factor transformation in pancreatic cancer. Arch. Surg. 134, 245–251 (1999).
  Article CAS PubMed Google Scholar
• Cobbs, C. S. et al. Inactivation of wild-type p53 protein function by reactive oxygen and nitrogen species in malignant glioma cells. Cancer Res. 63, 8670–8673 (2003).
  CAS PubMed Google Scholar
• Bentz, B. G., Haines, G. K. 3rd & Radosevich, J. A. Increased protein nitrosylation in head and neck squamous cell carcinogenesis. Head Neck 22, 64–70 (2000).
  Article CAS PubMed Google Scholar
• Dairou, J., Dupret, J. M. & Rodrigues-Lima, F. Impairment of the activity of the xenobiotic-metabolizing enzymes arylamine _N_-acetyltransferases 1 and 2 (NAT1/NAT2) by peroxynitrite in mouse skeletal muscle cells. FEBS Lett. 579, 4719–4723 (2005).
  Article CAS PubMed Google Scholar
• Ekmekcioglu, S. et al. Inducible nitric oxide synthase and nitrotyrosine in human metastatic melanoma tumors correlate with poor survival. Clin. Cancer Res. 6, 4768–4775 (2000).
  CAS PubMed Google Scholar
• Kinnula, V. L. et al. Ultrastructural and chromosomal studies on manganese superoxide dismutase in malignant mesothelioma. Am. J. Respir. Cell Mol. Biol. 31, 147–153 (2004).
  Article CAS Google Scholar
• Nakamura, Y. et al. Nitric oxide in breast cancer: induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis. Clin. Cancer Res. 12, 1201–1207 (2006).
  Article CAS PubMed Google Scholar
• Bronte, V. et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J. Exp. Med. 201, 1257–1268 (2005). This paper shows that peroxynitrite could be involved in T-2011 cell suppression in tumour tissues.
  Article CAS PubMed PubMed Central Google Scholar
• Nagaraj, S. et al. Altered recognition of antigen is a novel mechanism of CD8+ T cell tolerance in cancer. Nature Med. 13, 828–835 (2007). This paper describes the mechanism of MDSC-mediated CD8+T-2011 cell tolerance that involves post-translational modification of the TCR by peroxynitrite.
  Article CAS PubMed Google Scholar
• Dugast, A. S. et al. Myeloid-derived suppressor cells accumulate in kidney allograft tolerance and specifically suppress effector T cell expansion. J. Immunol. 180, 7898–7906 (2008).
  Article CAS PubMed Google Scholar
• Kusmartsev, S., Li, Y. & Chen, S.-H. Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. J. Immunol. 165, 779–785 (2000).
  Article CAS PubMed Google Scholar
• Watanabe, S. et al. Tumor-induced CD11b+Gr-1+ myeloid cells suppress T cell sensitization in tumor-draining lymph nodes. J. Immunol. 181, 3291–3300 (2008).
  Article CAS PubMed Google Scholar
• Stoll, S., Delon, J., Brotz, T. M. & Germain, R. N. Dynamic imaging of T cell–dendritic cell interactions in lymph nodes. Science 296, 1873–1876 (2002).
  Article PubMed Google Scholar
• Miller, M. J., Safrina, O., Parker, I. & Cahalan, M. D. Imaging the single cell dynamics of CD4+ T cell activation by dendritic cells in lymph nodes. J. Exp. Med. 200, 847–856 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Gabrilovich, D. I., Velders, M., Sotomayor, E. & Kast, W. M. Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J. Immunol. 166, 5398–5406 (2001).
  Article CAS PubMed Google Scholar
• Willimsky, G. et al. Immunogenicity of premalignant lesions is the primary cause of general cytotoxic T lymphocyte unresponsiveness. J. Exp. Med. 205, 1687–1700 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Monu, N. & Frey, A. B. Suppression of proximal T cell receptor signaling and lytic function in CD8+ tumor-infiltrating T cells. Cancer Res. 67, 11447–11454 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Fricke, I. et al. Vascular endothelial growth factor-trap overcomes defects in dendritic cell differentiation but does not improve antigen-specific immune responses. Clin. Cancer Res. 13, 4840–4848 (2007).
  Article CAS PubMed Google Scholar
• Antonia, S. J. et al. Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. Clin. Cancer Res. 12, 878–887 (2006).
  Article CAS PubMed Google Scholar
• Mantovani, A., Sozzani, S., Locati, M., Allavena, P. & Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23, 549–555 (2002).
  Article CAS PubMed Google Scholar
• Muller, A. J. & Prendergast, G. C. Indoleamine 2, 3-dioxygenase in immune suppression and cancer. Curr. Cancer Drug Targets 7, 31–40 (2007).
  Article CAS PubMed Google Scholar
• Hengesbach, L. & Hoag, K. Physiological concentrations of retinoic acid favor myeloid dendritic cell development over granulocyte development in cultures of bone marrow cells from mice. J. Nutr. 134, 2653–2659 (2004).
  Article CAS PubMed Google Scholar
• Kuwata, T. et al. Vitamin A deficiency in mice causes a systemic expansion of myeloid cells. Blood 95, 3349–3356 (2000).
  CAS PubMed Google Scholar
• Walkley, C., Yuan, Y., Chandraratna, R. & McArthur, G. Retinoic acid receptor antagonism in vivo expands the numbers of precursor cells during granulopoiesis. Leukemia 16, 1763–1772 (2002).
  Article CAS PubMed Google Scholar
• Kusmartsev, S. et al. All-_trans_-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res. 63, 4441–4449 (2003).
  CAS PubMed Google Scholar
• Nefedova, Y. et al. Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res. 67, 11021–11028 (2007).
  Article CAS PubMed Google Scholar
• Lathers, D., Clark, J., Achille, N. & Young, M. Phase 1B study to improve immune responses in head and neck cancer patients using escalating doses of 25-hydroxyvitamin D3. Cancer Immunol. Immunother. 53, 422–430 (2004).
  Article CAS PubMed Google Scholar
• Fricke, I. et al. Treatment of cancer patients with VEGF-Trap overcomes defects in DC differentiation but is insufficient to improve antigen-specific immune responses. Clin. Cancer Res. 13, 4840–4848 (2007).
  Article CAS PubMed Google Scholar
• Kusmartsev, S. et al. Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma. J. Immunol. 181, 346–353 (2008).
  Article CAS PubMed Google Scholar
• Melani, C., Sangaletti, S., Barazzetta, F. M., Werb, Z. & Colombo, M. P. Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma. Cancer Res. 67, 11438–11446 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Talmadge, J. E. et al. Chemoprevention by cyclooxygenase-2 inhibition reduces immature myeloid suppressor cell expansion. Int. Immunopharmacol. 7, 140–151 (2007).
  Article CAS PubMed Google Scholar
• Zea, A. H. et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. 65, 3044–3048 (2005).
  Article CAS PubMed Google Scholar
• Serafini, P. et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J. Exp. Med. 203, 2691–2702 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• De Santo, C. et al. Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proc. Natl Acad. Sci. USA 102, 4185–4190 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Suzuki, E., Kapoor, V., Jassar, A. S., Kaiser, L. R. & Albelda, S. M. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin. Cancer Res. 11, 6713–6721 (2005). References 21 and 104–106 show different therapeutic options of eliminating MDSCs or their activity for the treatment of cancer.
  Article CAS PubMed Google Scholar
• Ko, H. J. et al. A combination of chemoimmunotherapies can efficiently break self-tolerance and induce antitumor immunity in a tolerogenic murine tumor model. Cancer Res. 67, 7477–7486 (2007).
  Article CAS PubMed Google Scholar
• Ishida, T. et al. Dendritic cells transduced with wild type p53 gene elicit potent antitumor immune responses. Clinic. Exper. Immunol. 117, 244–251 (1999).
  Article CAS Google Scholar
• Ishida, T., Oyama, T., Carbone, D. & Gabrilovich, D. I. Defective function of Langerhans cells in tumor-bearing animals is the result of defective maturation from hematopoietic progenitors. J. Immunol. 161, 4842–4851 (1998).
  CAS PubMed Google Scholar
• Shojaei, F. & Ferrara, N. Refractoriness to antivascular endothelial growth factor treatment: role of myeloid cells. Cancer Res. 68, 5501–5504 (2008).
  Article CAS PubMed Google Scholar
• van Cruijsen, H. et al. Defective differentiation of myeloid and plasmacytoid dendritic cells in advanced cancer patients is not normalized by tyrosine kinase inhibition of the vascular endothelial growth factor receptor. Clin. Dev. Immunol. 2007, 17315 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Shojaei, F. et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nature Biotechnol. 25, 911–920 (2007).
  Article CAS Google Scholar
• Bronte, V. et al. Unopposed production of granulocyte–macrophage colony-stimulating factor by tumors inhibits CD8+ T cell responses by dysregulating antigen-presenting cellmaturation. J. Immunol. 162, 5728–5737 (1999).
  CAS PubMed Google Scholar
• Young, M., Wright, M. & Young, M. Antibodies to colony-stimulating factors block Lewis lung carcinoma cell stimulation of immune-suppressive bone marrow cells. Cancer Immunol. Immunother. 33, 146–152 (1991).
  Article CAS PubMed Google Scholar
• Young, M. R. & Lathers, D. M. Myeloid progenitor cells mediate immune suppression in patients with head and neck cancers. Int. J. Immunopharmacol. 21, 241–252 (1999).
  Article CAS PubMed Google Scholar
• Fu, Y., Watson, G., Jimenez, J., Wang, Y. & Lopez, D. Expansion of immunoregulatory macrophages by granulocyte–macrophage colony-stimulating factor derived from a murine mammary tumor. Cancer Res. 50, 227–234 (1990).
  CAS PubMed Google Scholar
• Daud, A. I. et al. Phenotypic and functional analysis of dendritic cells and clinical outcome in patients with high-risk melanoma treated with adjuvant granulocyte macrophage colony-stimulating factor. J. Clin. Oncol. 26, 3235–3241 (2008).
  Article CAS PubMed Google Scholar
• Filipazzi, P. et al. Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte–macrophage colony-stimulation factor-based antitumor vaccine. J. Clin. Oncol. 25, 2546–2553 (2007).
  Article CAS PubMed Google Scholar
• Sawanobori, Y. et al. Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood 111, 5457–5466 (2008).
  Article CAS PubMed Google Scholar
• Menetrier-Caux, C. et al. 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 (1998).
  CAS PubMed Google Scholar
• Birkle, S., Zeng, G., Gao, L., Yu, R. K. & Aubry, J. Role of tumor-associated gangliosides in cancer progression. Biochimie 85, 455–463 (2003).
  Article CAS PubMed Google Scholar
• Shurin, G. V. et al. Neuroblastoma-derived gangliosides inhibit dendritic cell generation and function. Cancer Res. 61, 363–369 (2001).
  CAS PubMed Google Scholar
• Biswas, S. K. et al. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation). Blood 107, 2112–2122 (2006).
  Article CAS PubMed Google Scholar
• Mazzoni, A. et al. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J. Immunol. 168, 689–695 (2002).
  Article CAS PubMed Google Scholar
• Huang, B. et al. CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Lett. 252, 86–92 (2007).
  Article CAS PubMed Google Scholar
• Markiewski, M. M. et al. Modulation of the antitumor immune response by complement. Nature Immunol. 9, 1225–1235 (2008).
  Article CAS Google Scholar
• Yang, L. et al. Abrogation of TGFβ signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13, 23–35 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Young, M. R. I., Wright, M. A., Matthews, J. P., Malik, I. & Pandit, R. Suppression of T cell proliferation by tumor-induced granulocyte-macrophage progenitor cells producing transforming growth factor-beta and nitric oxide. J. Immunol. 156, 1916–1921 (1996).
  CAS PubMed Google Scholar
• Beck, C., Schreiber, K., Schreiber, H. & Rowley, D. A. C-kit+ FcR+ myelocytes are increased in cancer and prevent the proliferation of fully cytolytic T cells in the presence of immune serum. Eur. J. Immunol. 33, 19–28 (2003).
  Article CAS PubMed Google Scholar
• Bunt, S. K., Sinha, P., Clements, V. K., Leips, J. & Ostrand-Rosenberg, S. Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J. Immunol. 176, 284–290 (2006).
  Article CAS PubMed Google Scholar
• Song, X. et al. CD11b+/Gr-1+ immature myeloid cells mediate suppression of T cells in mice bearing tumors of IL-1β-secreting cells. J. Immunol. 175, 8200–8208 (2005).
  Article CAS PubMed Google Scholar
• Yang, L. et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6, 409–421 (2004).
  Article CAS PubMed Google Scholar
• Drevets, D. A. et al. The Ly-6Chigh monocyte subpopulation transports Listeria monocytogenes into the brain during systemic infection of mice. J. Immunol. 172, 4418–4424 (2004).
  Article CAS PubMed Google Scholar