Myeloid-derived suppressor cell

Transcription

1 JJIAO 30 4 : , 2012 Myeloid-derived suppressor cell 1 1 Myeloid-derived suppressor cells MDSC MDSC T MDSC MDSC MDSC MDSC MDSC myeloid-derived suppressor cells MDSC MDSC, myeloid-derived suppressor cells; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-10, interleukin-10; IL-12, interleukin 12; TGF-β, transforming growth factor β; IFN-γ, interferon-γ; GM-CSF, granulocyte macrophage colonystimulating factor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; NK, natural killer, SSC, sideward scatter; ROS, reactive oxygen species; NO, nitric oxide; inos, inducible nitric oxide synthase; ATRA, all-trans retinoic acid; COX2, cyclooxigenase 2; NSAIDs, non-steroidal antiinflammatory drugs; ED, erectile dysfunction; PDE5, phosphodiesterase-5; MMP9, matrix metalloproteinase 9; MHC, major histocompatibility complex endothelial cells fibroblast adipocytes macrophage granulocytes immature myeloid cells cell-to-cell contact tumor-derived factors myeloid origin myeloid-derived suppressor cells: MDSC 1,2) MDSC TEL: FAX: tikamatu@gunma-u.ac.jp 3,4) 1990 MDSC MDSC CD11b + Gr-1 + 5,6) MDSC heterogeneous 1 1 MDSC 2012 Japan Society of Immunology & Allergology in Otolaryngology

2 272 Myeloid-derived suppressor cell 1 MDSC T M2 type 1 MDSC Tumor-derived factor 4 T Mφ NK NKT 5 MDSC phenotype MDSC heterogeneous MDSC IL-1β IL-6 prostaglandin E2 GM-CSF VEGF MDSC MDSC T MDSC heterogeneous CD11b + Gr1 + MDSC CD11b + Gr-1 high granulocyte-like CD11b + Ly-6G + Ly6C low CD11b + Gr-1 low monocyte-like CD11b + Ly-6G Ly6C high 7) MDSC Gr-1 MDSC CD11b + CD14 CD33 + Lin HLA- DR CD33 + 8,9) MDSC 2 granulocytic MDSC monocytic MDSC CD11b CD33 HLA-DR granulocytic MDSC CD15 monocytic MDSC CD14 10) CD115 CD124 VEGF-R 11 13) MDSC Lin HLA-DR 14) CD11b + CD14 CD ,16) SSC high CD66b + 17) CD14 + HLA-DR 18)

3 JJIAO 2012: MDSC 1 L-arginine metabolism arginase L-arginine L-arginine CD3ζ T 2 TGF-β, IL-10, VEGF T CTL MDSC 3 T naïve T L-selectin 4 T CD4 + CD25 + Foxp3 + T 5 matrix metalloproteinase 9 6 Reactive oxygen species ROS nitric oxide NO ROS NO ROS myeloid cells NO T MDSC MDSC 2 1 T L-arginine arginase L-ornithine MDSC T L-arginine MDSC arginase L-arginine L-arginine L-arginine T CD3ζ 19) 2 TGF-β IL-10 20,21) T NK T T IL-10 IL-12 M1 type M2 type M2 polarization MDSC VEGF MDSC MDSC 22) 3 T T naïve T L-selectin CD62L Hanson MDSC naïve T L-selectin 23) 4 T MDSC T 24 26) IL-10 TGF-β arginase CD40 CD80 MDSC Hoechst CD14 + HLA-DR /low CD4 + CD25 + Foxp3 + T 27) MDSC T 5 MDSC matrix metalloproteinase 9 MMP9 28) 6 reactive oxygen species ROS nitric oxide NO ROS NO MDSC MDSC ROS MDSC 29) ROS DNA MDSC MDSC 5) T CD8 T

4 274 Myeloid-derived suppressor cell 3 MDSC Phenotype References CD ) CD14 + HLA-DR 18) Lin HLA-DR 14), 33) CD11b + CD14 CD ), 16) SSC high CD66b + 17) MHC T ROS 30) NO MHC class II 31) T T 19) CD14 + HLA-DR arginase TGF-β 27) CD14 + HLA-DR TGF-β arginase 20) MDSC MDSC MDSC MDSC MDSC 32) MDSC 3 Almand Lin HLA-DR Lin HLA-DR 14,33) Lin HLA-DR Lin HLA-DR VEGF Lin HLA-DR Lin HLA-DR VEGF Corzo stage III CD11b + CD14 CD33 + MDSC MDSC ROS 15) MDSC MDSC ROS inducible nitric oxide synthase inos NO T 16) MDSC MDSC Brandau neutrophilic MDSC SSC high CD66b + T IFN-γ CXCR1 CXCR2 17) monocytic MDSC CD14 + HLA-DR 18) CD14 + HLA-DR CD14 + CD14 + HLA-DR monocytic MDSC CD14 + HLA-DR T IFN-γ CD14 + HLA-DR CD14 + HLA-DR + CD86 PD-L1 T monocytic MDSC 20,27) CD14 + HLA-DR + TGF-β arginase I monocytic MDSC MDSC MDSC T MDSC heterogeneity 4 1 MDSC all-trans retinoic acid ATRA MDSC 14,34)

5 JJIAO 2012: MDSC 1 All-trans retinoic acid ATRA 25-hydroxyvitamin D3 2 Docetaxel 5-FU Gemcitabine 3 Bevacuzumab VEGF-Trap Sunitinib 4 COX2 inhibitor PDE5 inhibitor Sildenafil Aminobiphosphonate Zoledronate ROS MDSC M1 MDSC MDSC VEGF VEGF-A VEGFR arginase I IL-4Rα, arginase I, inos MMP9 T Mirza ATRA Lin HLA-DR CD33 + Lin HLA-DR + 35) T ATRA MDSC ROS 34) MDSC 25-hydroxyvitamin D3 25-hydroxyvitamin D3 phase IB CD34 + MDSC HLA-DR + IFN-γ IL-12 36) 2 MDSC MDSC 37) 5-FU MDSC CD8 + T 38) MDSC CD4 + T CD8 + T NK B 39) MDSC CD8 + T NK MDSC - MDSC 40) MDSC heterogeneity MDSC phenotype MDSC 3 VEGF MDSC VEGF MDSC 33,41) anti-vegf bevacizumab anti-vegf VEGF MDSC 41) VEGF receptor 1 receptor 2 VEGF Trap VEGF-A MDSC 42) VEGFR sunitinib MDSC MDSC MDSC Th1 43) 4 COX2 MDSC NSAIDs COX2 inhibitor

6 276 Myeloid-derived suppressor cell MDSC arginase I 44) ED phosphoesterase 5 (PDE5) inhibitor (Sildenafil) MDSC IL-4Rα arginase I inos 45) matrix metalloproteinase 9 MMP9 MDSC MMP9 aminobiphosphonate Zoledronate MMP9 aminobiphosphonate MMP9 MDSC 46) MDSC MDSC heterogeneity MDSC MDSC MDSC MDSC MDSC 1) Kusmartsev S, Gabrilovich DI. Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother. 2006; 55(3): ) Kusmartsev S, Gabrilovich DI. Effect of tumor-derived cytokines and growth factors on differentiation and immune suppressive features of myeloid cells in cancer. Cancer Metastasis Rev. 2006; 25(3): ) Cuenca AG, Delano MJ, et al. A paradoxical role for myeloidderived suppressor cells in sepsis and trauma. Mol Med. 2011; 17(3 4): ) Haverkamp JM, Crist SA, et al. In vivo suppressive function of myeloid-derived suppressor cells is limited to the inflammatory site. Eur J Immunol. 2011; 41(3): ) Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009; 9(3): ) Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest. 2007; 117(5): ) Youn JI, Nagaraj S, et al. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol. 2008; 181(8): ) Zea A, Rodriguez PC, et al. Arginase-producing myeloid-derived suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. 2005; 65(8): ) Kusmartsev S, Su Z, et al. Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma. Clin Cancer Res. 2008; 14(24): ) Greten TF, Manns MP, et al. Myeloid derived suppressor cells in human diseases. Int Immunopharmacol. 2011; 11(7): ) Mandruzzato S, Solito S, et al. IL-4Ralpha+ myeloid-derived suppressor cell expansion in cancer patients. J Immunol. 2009; 182(10): ) Dugast AS, Haudebourg T, et al. Myeloid-derived suppressor cells accumulate in kidney allograft tolerance and specifically suppress effector T cell expansion. J Immunol. 2008; 180(12): ) Kusmartsev S, Eruslanov E, et al. Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma. J Immunol. 2008; 181(1): ) Almand B, Clark JI, et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2001; 166(1): ) Corzo CA, Cotter MJ, et al. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J Immunol. 2009; 182(9): ) Corzo CA, Condamine T, et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor micro environments. J Exp Med. 2010; 207(11): ) Brandau S, Trellakis S, et al. Myeloid-derived suppressor cells in the peripheral blood of cancer patients contain a subset of immature neutrophils with impaired migratory properties. J Leukoc Biol. 2011; 89(2): ) Chikamatsu K, Sakakura K, et al. Immunosuppressive activity of CD14+HLA-DR- cells in squamous cell carcinoma of the head and neck. Cancer Sci. 2012; 103(6): ) Bronte V, Serafini P, et al. L-arginine metabolism in myeloid cell controls T-lymphocyte functions. Trend Immunol. 2003; 24(6): ) Filipazzi P, Valenti R, 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 factorbased antitumor vaccine. J Clin Oncol. 2007; 25(18): ) Obermajer N, Muthuswamy R, et al. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood. 2011; 118(20):

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8 278 Myeloid-derived suppressor cell Characterization and clinical implications of myeloid-derived suppressor cells in head and neck cancer Kazuaki Chikamatsu 1 1 Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine ABSTRACT Myeloid-derived suppressor cells (MDSC) represent a heterogeneous population and have the potential to suppress immune responses via diverse mechanisms including the production of immunosuppressive cytokines, arginase I, reactive oxygen species, and nitric oxide. Due to the lack of specific markers, human MDSC are still poorly defined. Recent studies suggest that in head and neck cancer, abnormal accumulation of MDSC in peripheral blood and tumor sites might contribute as an important mechanism of tumor immune evasion. This article reviews the characterization and immune suppressive mechanisms mediated by MDSC. Moreover, clinical implications in patients with head and neck cancer, as well as the development of novel strategies to efficiently overcome immune suppression by MDSC are also discussed. Key words: myeloid-derived suppressor cells (MDSC), immune suppression, anti-tumor immune responses, immunotherapy