Skip to main content

Advertisement

SpringerLink
Log in

Role Of Immature Myeloid Cells in Mechanisms of Immune Evasion In Cancer

  • Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Tumor affects myelopoiesis by inhibiting the process of differentiation/maturation of antigen-presenting cells from their myeloid precursors and by stimulating an accumulation of immature myeloid cells in cancer patients and tumor-bearing mice. These immature myeloid cells can contribute greatly to tumor progression and promote tumor evasion from immune attack: i) by inhibiting development of adaptive immune responses against tumor in lymphoid organs; ii) by migrating into tumor site and differentiating there into highly immune suppressive tumor-associated macrophages. Immature myeloid cells and tumor-associated macrophages utilize different JAK/STAT signaling pathways and different mechanisms to control T cell responses, which include increased production of TGF-beta, reactive oxygen species, peroxynitrites, as well as enhanced L-arginine metabolism. Understanding of precise mechanisms, which tumors use to affect differentiation of APC from myeloid cell precursors and inhibit T cell responses, could help to develop new approaches for cancer therapy and substantially improve efficiency of existing cancer vaccination strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

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

    PubMed  CAS  Google Scholar 

  2. Almand B, Resser J, Lindman B, Nadaf S, Clark J, Kwon E, Carbone D and Gabrilovich D (2000) Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 6:1755–1766

    PubMed  CAS  Google Scholar 

  3. Atochina O, Daly-Angel T, Piskorska D and Harn D (2001) A shistosome expressed immunomodulatory glycoconjugate expand peritoneal Gr1+ macrophages that suppress naïve CD4+ T cell proliferation via an interferon-gamma and nitric oxide dependent mechanism. J Immunol 167:4293–4302

    PubMed  CAS  Google Scholar 

  4. Balkwill F and Mantovani A (2001) Inflammation and cancer:back to Virchow? Lancet 357(9255):539–545

    Article  PubMed  CAS  Google Scholar 

  5. Beck C, Schreiber K, Schreiber H and Rowley D (2001) 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(1):19–28

    Article  Google Scholar 

  6. Boucher JL, Moali C and Tenu JP (1999) Nitric oxyde byosynthesis, nitric oxide synthase inhibitors and arginase competition for L-arginine utilization. Cell Mol Life Sci 55:1015–1028

    Article  PubMed  CAS  Google Scholar 

  7. Bromberg J (2002) Stat proteins and oncogenesis. J Clin Invest 109:1139–1142

    Article  PubMed  CAS  Google Scholar 

  8. Bronte V, Apolloni E, Cabrelle A, Ronca R, Serafini P, Zamboni P, Restifo N and Zanovello P (2000) Identification of a CD11b(+)/Gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells. Blood 96:3838

    PubMed  CAS  Google Scholar 

  9. Bronte V, Casic T, Gri G, Gallana K, Borsellino G, Marrigo I, Battistini L, Iafrate M, Prayer-Galletti U, Pagano F and Viola A (2005) Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J Exp Med 201(8):1257–1268

    Article  PubMed  CAS  Google Scholar 

  10. Bronte V, Chappell DB, Apolloni E, Cabrelle A, Wang M, Hwu P and Restifo NP (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

    PubMed  CAS  Google Scholar 

  11. Bronte V, Serafini P, Appoloni E and Zanovello P (2001) Tumor-induced immune dysfunctions caused by myeloid suppressor cells. J Immunoth 24:431–446

    Article  CAS  Google Scholar 

  12. Bronte V, Serafini P, De Santo C, Marigo I, Tosello V, Mazzoni A, Segal DM, Staib C, Lowel M, Sutter G, Colombo MP and Zanovello P (2003) IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J Immunol 170(1):270–278

    PubMed  CAS  Google Scholar 

  13. Bronte V, Wang M, Overwijk W, Surman D, Pericle F, Rosenberg SA and Restifo NP (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

    PubMed  CAS  Google Scholar 

  14. Cauley L, Miller E, Yen M and Swain S (2000) Superantigen-induced CD4 T cell tolerance mediated by myeloid cells and IFN-gamma. J Immunol 165:6056

    PubMed  CAS  Google Scholar 

  15. Cheng F, Wang HW, Cuenca A, Huang M, Ghansah T, Brayer J, Kerr WG, Takeda K, Akira S, Schoenberger SP, Yu H, Jove R and Sotomayor EM (2003) A critical role for Stat3 signaling in immune tolerance. Immunity 19:425–436

    Article  PubMed  CAS  Google Scholar 

  16. De Santo C, Serafini P, Marigo I, Dolcetti L, Bolla M, P DS, Melani C, Guiducci C, Colombo M, Iezzi M, Musiani P, Zanovello P and Bronte V (2005) Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination. Proc Natl Acad Sci U S A 102(11):4185–4190

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  18. Gabrilovich D, Cheng P, Fan Y, Yu B, Nikitina E, Sirotkin A, Shurin M, Oyama T, Adachi Y, Nadaf S, Carbone DP and Skoultchi A (2002) H1o Histone and Differentiation of Dendritic Cells A Molecular Target for Tumor-Derived Factors. J Leuk Biol 72:285–296

    CAS  Google Scholar 

  19. Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S and Carbone DP (1998) Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92(11):4150–4166

    PubMed  CAS  Google Scholar 

  20. Gabrilovich DI, Velders M, Sotomayor E and Kast WM (2001) Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J Immunol 166:5398–5406

    PubMed  CAS  Google Scholar 

  21. Hengesbach L and Hoag K (2004) Physiological concentrations of retinoic acid favor myeloid dendritic cell development over granulocyte development in cultures of bone marrow cells from mice. J Nutr 134(10): 2653–2659

    PubMed  CAS  Google Scholar 

  22. Hestdal K, Ruscetti F, Ihle J, Jacobsen S, Dubois C, Kopp W, Longo D and Keller J (1991) Characterization and regulation of RB6-8C5 antigen expression on murine bone marrow cells. J Immunol 147(1):22–28

    PubMed  CAS  Google Scholar 

  23. Kusmartsev S, Cheng F, Yu B, Nefedova Y, Sotomayor E, Lush R and Gabrilovich DI (2003) All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res 63:4441–4449

    PubMed  CAS  Google Scholar 

  24. Kusmartsev S and Gabrilovich D (2005) STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J Immunol 174(8): 4880–4891

    PubMed  CAS  Google Scholar 

  25. Kusmartsev S and Gabrilovich DI (2003) Inhibition of myeloid cell differentiation in cancer:The role of reactive oxygen species. J Leukoc Biol 74(2):186–196

    Article  PubMed  CAS  Google Scholar 

  26. Kusmartsev S, Li Y and Chen S-H (2000) Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. J Immunol 165:779–785

    PubMed  CAS  Google Scholar 

  27. Kusmartsev S, Nefedova Y, Yoder D and Gabrilovich DI (2004) Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol 172(2):989–999

    PubMed  CAS  Google Scholar 

  28. Kuwata T, Wang I, Tamura T, Ponnamperuma R, Levine R, Holmes K, Morse H, De Luca L and Ozato K (2000) Vitamin A deficiency in mice causes a systemic expansion of myeloid cells. Blood 95(11):3349–3356

    PubMed  CAS  Google Scholar 

  29. Lathers D, Clark J, Achille N and Young M (2004) Phase 1B study to improve immune responses in head and neck cancer patients using escalating doses of 25-hydroxyvitamin D3. Cancer Immunol Immunother 53(5):422–430

    Article  PubMed  CAS  Google Scholar 

  30. Li Q, Pan PY, Gu P, Xu D and Chen SH (2004) Role of immature myeloid Gr-1+ cells in the development of antitumor immunity. Cancer Res 64(3):1130–1139

    Article  PubMed  CAS  Google Scholar 

  31. Liu Y, Van Ginderachter J, Brys L, De Baetselier P, Raes G and Geldhof A (2003) Nitric oxide-independent CTL suppression during tumor progression:association with arginase-producing (M2) myeloid cells. J Immunol 170(10):5064–5074

    PubMed  CAS  Google Scholar 

  32. Mantovani A, Sozzani S, Locati M, Allavena P and Sica A (2002) Macrophage polarization:tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555

    Article  PubMed  CAS  Google Scholar 

  33. Melani C, Chiodoni C, Forni G and Colombo MP (2003) Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity. Blood 102(6):2138–2145

    Article  PubMed  CAS  Google Scholar 

  34. Mencacci A, Montagnoli C, Bacci A, Cenci E, Pitzurra L, Spreca A, Kopf M, Sharpe A and Romani L (2002) CD80+Gr-1+ myeloid cells inhibit development of antifungal Th1 immunity in mice with candidiasis. J Immunol 169(6):3180–3190

    PubMed  CAS  Google Scholar 

  35. Menetrier-Caux C, Thomachot MC, Alberti L, Montmain G and Blay JY (2001) IL-4 prevents the blockade of dendritic cell differentiation induced by tumor cells. Cancer Res 61(7):3096–3104

    PubMed  CAS  Google Scholar 

  36. Nefedova Y, Huang M, Kusmartsev S, Bhattacharya R, Cheng P, Salup R, Jove R and Gabrilovich D (2004) Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J Immunol 172(1):464–474

    PubMed  CAS  Google Scholar 

  37. Ostrand-Rosenberg S, Clements VK, Terabe M, Park JM, Berzofsky JA and Dissanayake SK (2002) Resistance to metastatic disease in STAT6-deficient mice requires hemopoietic and nonhemopoietic cells and is IFN-gamma dependent. J Immunol 169(10):5796–5804

    PubMed  CAS  Google Scholar 

  38. Otsuji M, Kimura Y, Aoe T, Okamoto Y and Saito T (1996) Oxidative stress by tumor-derived macrophages suppresses the expression of CD3 zeta chain of T-cell receptor complex and antigen-specific T-cell responses. Proc Natl Acad Sci USA 93:13119–13124

    Article  PubMed  CAS  Google Scholar 

  39. Pandit R, Lathers D, Beal N, Garrity T and Young M (2000) CD34+ immune suppressive cells in the peripheral blood of patients with head and neck cancer. Ann Otol Rhinol Laryngol 109:749–754

    PubMed  CAS  Google Scholar 

  40. Pelaez B, Campillo J, Lopez-Asenjo J and Subiza J (2001) Cyclophosphamide induces the development of early myeloid cells suppressing tumor growth by a nitric oxide-dependent mechanism. J Immunol 166:6608

    PubMed  CAS  Google Scholar 

  41. Pollard J (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4(1):71–78

    Article  PubMed  CAS  Google Scholar 

  42. Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, Delgado A, Correa , Brayer J, Sotomayor EM, Antonia S, Ochoa JB and Ochoa AC (2004) Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 64(16):5839–5849

    Article  PubMed  CAS  Google Scholar 

  43. Rodriguez PC, Zea AH, Culotta KS, Zabaleta J, Ochoa JB and Ochoa AC (2002) Regulation of T cell receptor CD3zeta chain expression by L-arginine. J Biol Chem 277:21123–21129

    Article  PubMed  CAS  Google Scholar 

  44. Rodriguez PC, Zea AH, DeSalvo J, Culotta KS, Zabaleta J, Quiceno DG, Ochoa JB and Ochoa AC (2003) L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. J Immunol 171(3):1232–1239

    PubMed  CAS  Google Scholar 

  45. Saio M, Radoja S, Marino M and Frey AB (2001) Tumor-infiltrating macrophages induce apoptosis in activated CD8(+) T cells by a mechanism requiring cell contact and mediated by both the cell-associated form of TNF and nitric oxide. J Immunol 167(10):5583–5593

    PubMed  CAS  Google Scholar 

  46. Salvadori S, Martinelli G and Zier K (2000) Resection of solid tumors reverses T cell defects and restores protective immunity. J Immunol 164:2214

    PubMed  CAS  Google Scholar 

  47. Sauer H, Wartenberg M and Hescheler J (2001) Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell Physiol Biochem 11:173–186

    Article  PubMed  CAS  Google Scholar 

  48. Schmielau J and Finn OJ (2001) 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

    PubMed  CAS  Google Scholar 

  49. Schreck R, Albermann K and Baeuerle PA (1992) Nuclear factor kappa B:an oxidative stress-responsive transcription factor of eukaryotic cells (a review). Free Radic Res Commun 17:221–237

    Article  PubMed  CAS  Google Scholar 

  50. Seung L, Rowley D, Dubeym P and Schreiber H (1995) Synergy between T-cell immunity and inhibition of paracrine stimulation causes tumor rejection. Proc Natl Acad Sci U S A 92(14):6254–6258

    Article  PubMed  CAS  Google Scholar 

  51. Shankaran V, Ikeda H, Bruce A, White J, Swanson P, Old L and Schreiber R (2001) IFN-gamma and lymphocytes prevent primary tumor development and shape tumor immunogenicity. Nature 410:1107–1111

    Article  PubMed  CAS  Google Scholar 

  52. Sinha P, Clements V and 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(2):636–645

    PubMed  CAS  Google Scholar 

  53. Subiza J, Vinuela J, Rodriguez R and De la Concha E (1989) Development of splenic natural suppressor (NS) cells in Ehrlich tumor-bearing mice. Int J Cancer 44:307–314

    Article  PubMed  CAS  Google Scholar 

  54. Terabe M, Matsui S, Park JM, Mamura M, Noben-Trauth N, Donaldson DD, Chen W, Wahl SM, Ledbetter S, Pratt B, Letterio JJ, Paul WE and Berzofsky JA (2003) Transforming growth factor-beta 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(11):1741–1752

    Article  PubMed  CAS  Google Scholar 

  55. Walkley C, Yuan Y, Chandraratna R and McArthur G (2002) Retinoic acid receptor antagonism in vivo expands the numbers of precursor cells during granulopoiesis. Leukemia 16(9):1763–1772

    Article  PubMed  CAS  Google Scholar 

  56. Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D, Dalton W, Jove R, Pardoll D and Yu H (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10(1):48–54

    Article  PubMed  Google Scholar 

  57. Wiers K, Lathers D, Wright M and Young M (2000) Vitamin D3 treatment to diminish the levels of immune suppressive CD34+ cells increases the effectiveness of adoptive immunotherapy. J Immunother 23(1):115–124

    Article  PubMed  CAS  Google Scholar 

  58. Wu G and Morris SM (1998) Arginine metabolism:nitric oxide and beyond. Biochem J 336:1–17

    PubMed  CAS  Google Scholar 

  59. Yang L, DeBusk L, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, Matrisian L, Carbone D and Lin P (2004) Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6(4):409–421

    Article  PubMed  CAS  Google Scholar 

  60. Young M (2004) Tumor skewing of CD34+ progenitor cell differentiation into endothelial cells. Int J Cancer 109(4):516–524

    Article  PubMed  CAS  Google Scholar 

  61. Young M, Ihm J, Lozano Y, Wright M and Prechel M (1995) Treating tumor-bearing mice with vitamin D3 diminishes tumor-induced myelopoiesis and associated immunosuppression, and reduces tumor metastasis and recurrence. Cancer Immunol Immunother 41(1):37–45

    PubMed  CAS  Google Scholar 

  62. Young MR and Lathers DM (1999) Myeloid progenitor cells mediate immune suppression in patients with head and neck cancers. Int J Immunopharmacol 21:241–252

    Article  PubMed  CAS  Google Scholar 

  63. Young MRI, Wright MA, Matthews JP, Malik I and Pandit R (1996) Suppression of T cell proliferation by tumor-induced granulocyte-macrophage progenitor cells producing transforming growth factor- b and nitric oxide. J Immunol 156:1916–1921

    PubMed  CAS  Google Scholar 

  64. Zea AH, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, Zabaleta J, McDermott D, Quiceno D, Youmans A, O’Neill A, Mier J and Ochoa AC (2005) Arginase-producing myeloid suppressor cells in renal cell carcinoma patients:a mechanism of tumor evasion. Cancer Res 65(8): 3044–3048

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. H. Lee Moffitt Cancer Center and Research Institute and The Department of Interdisciplinary Oncology, University of South Florida, MRC 2067, 12902 Magnolia Dr, Tampa, 33612, FL,  

    Sergei Kusmartsev & Dmitry I. Gabrilovich

Authors
  1. Sergei Kusmartsev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dmitry I. Gabrilovich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dmitry I. Gabrilovich.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kusmartsev, S., Gabrilovich, D.I. Role Of Immature Myeloid Cells in Mechanisms of Immune Evasion In Cancer. Cancer Immunol Immunother 55, 237–245 (2006). https://doi.org/10.1007/s00262-005-0048-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-005-0048-z

Keywords

Search

Navigation