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Published in:

01-07-2013 | Review

Myeloid-derived suppressor cells in breast cancer

Authors: Joseph Markowitz, Robert Wesolowski, Tracey Papenfuss, Taylor R. Brooks, William E. Carson III

Published in: Breast Cancer Research and Treatment | Issue 1/2013

Abstract

Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells defined by their suppressive actions on immune cells such as T cells, dendritic cells, and natural killer cells. MDSCs typically are positive for the markers CD33 and CD11b but express low levels of HLADR in humans. In mice, MDSCs are typically positive for both CD11b and Gr1. These cells exert their suppressive activity on the immune system via the production of reactive oxygen species, arginase, and cytokines. These factors subsequently inhibit the activity of multiple protein targets such as the T cell receptor, STAT1, and indoleamine-pyrrole 2,3-dioxygenase. The numbers of MDSCs tend to increase with cancer burden while inhibiting MDSCs improves disease outcome in murine models. MDSCs also inhibit immune cancer therapeutics. In light of the poor prognosis of metastatic breast cancer in women and the correlation of increasing levels of MDSCs with increasing disease burden, the purposes of this review are to (1) discuss why MDSCs may be important in breast cancer, (2) describe model systems used to study MDSCs in vitro and in vivo, (3) discuss mechanisms involved in MDSC induction/function in breast cancer, and (4) present pre-clinical and clinical studies that explore modulation of the MDSC–immune system interaction in breast cancer. MDSCs inhibit the host immune response in breast cancer patients and diminishing MDSC actions may improve therapeutic outcomes.

Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62(1):10–29

Soliman H (2010) Developing an effective breast cancer vaccine Cancer control. J Moffitt Cancer Cent 17(3):183–190

Soliman H (2013) Immunotherapy strategies in the treatment of breast cancer Cancer control. J Moffitt Cancer Cent 20(1):17–21

Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12(4):253–268PubMedCrossRef

Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174PubMedCrossRef

Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ (2009) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58(1):49–59PubMedCrossRef

Almand B, Resser JR, Lindman B, Nadaf S, Clark JI, Kwon ED, Carbone DP, Gabrilovich DI (2000) Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 6(5):1755–1766PubMed

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

Cole S, Montero A, Garret-Mayer E, Onicescu G, Vandenberg T, Hutchens S, Diaz-Montero C (2009) Elevated circulating myeloid derived suppressor cells (MDSC) are associated with inferior overall survival (OS) and correlate with circulating tumor cells (CTC) in patients with metastatic breast cancer. In: Thirty-second annual CTRC-AACR San Antonio breast cancer symposium: 2009. Cancer Research, San Antonio

10.

Montero AJ, Diaz-Montero CM, Deutsch YE, Hurley J, Koniaris LG, Rumboldt T, Yasir S, Jorda M, Garret-Mayer E, Avisar E et al (2012) Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer. Breast Cancer Res Treat 132(1):215–223PubMedCrossRef

11.

Wagner KU (2004) Models of breast cancer: quo vadis, animal modeling? Breast Cancer Res 6(1):31–38PubMedCrossRef

12.

Imaoka T, Nishimura M, Iizuka D, Daino K, Takabatake T, Okamoto M, Kakinuma S, Shimada Y (2009) Radiation-induced mammary carcinogenesis in rodent models: what’s different from chemical carcinogenesis? J Radiat Res 50(4):281–293PubMedCrossRef

13.

Fantozzi A, Christofori G (2006) Mouse models of breast cancer metastasis. Breast Cancer Res 8(4):212PubMedCrossRef

14.

Weinstein EJ, Kitsberg DI, Leder P (2000) A mouse model for breast cancer induced by amplification and overexpression of the neu promoter and transgene. Mol Med 6(1):4–16PubMed

15.

Habibi M, Kmieciak M, Graham L, Morales JK, Bear HD, Manjili MH (2009) Radiofrequency thermal ablation of breast tumors combined with intralesional administration of IL-7 and IL-15 augments anti-tumor immune responses and inhibits tumor development and metastasis. Breast Cancer Res Treat 114(3):423–431PubMedCrossRef

16.

Smith C, Chang MY, Parker KH, Beury DW, DuHadaway JB, Flick HE, Boulden J, Sutanto-Ward E, Soler AP, Laury-Kleintop LD et al (2012) IDO is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discov 2(8):722–735PubMedCrossRef

17.

Hennighausen L (2000) Mouse models for breast cancer. Breast Cancer Res 2(1):2–7PubMedCrossRef

18.

Kim JB, O’Hare MJ, Stein R (2004) Models of breast cancer: is merging human and animal models the future? Breast Cancer Res 6(1):22–30PubMedCrossRef

19.

Vargo-Gogola T, Rosen JM (2007) Modelling breast cancer: one size does not fit all. Nat Rev Cancer 7(9):659–672PubMedCrossRef

20.

Aslakson CJ, Miller FR (1992) Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res 52(6):1399–1405PubMed

21.

Boutte AM, McDonald WH, Shyr Y, Yang L, Lin PC (2011) Characterization of the MDSC proteome associated with metastatic murine mammary tumors using label-free mass spectrometry and shotgun proteomics. PLoS One 6(8):e22446PubMedCrossRef

22.

Donkor MK, Lahue E, Hoke TA, Shafer LR, Coskun U, Solheim JC, Gulen D, Bishay J, Talmadge JE (2009) Mammary tumor heterogeneity in the expansion of myeloid-derived suppressor cells. Int Immunopharmacol 9(7–8):937–948PubMedCrossRef

23.

Heppner GH, Miller FR, Shekhar PM (2000) Nontransgenic models of breast cancer. Breast Cancer Res 2(5):331–334PubMedCrossRef

24.

Le HK, Graham L, Cha E, Morales JK, Manjili MH, Bear HD (2009) Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. Int Immunopharmacol 9(7–8):900–909PubMedCrossRef

25.

Caligiuri I, Rizzolio F, Boffo S, Giordano A, Toffoli G (2012) Critical choices for modeling breast cancer in transgenic mouse models. J Cell Physiol 227(8):2988–2991PubMedCrossRef

26.

Mundy-Bosse BL, Lesinski GB, Jaime-Ramirez AC, Benninger K, Khan M, Kuppusamy P, Guenterberg K, Kondadasula SV, Chaudhury AR, La Perle KM et al (2011) Myeloid-derived suppressor cell inhibition of the IFN response in tumor-bearing mice. Cancer Res 71(15):5101–5110PubMedCrossRef

27.

Lu T, Ramakrishnan R, Altiok S, Youn JI, Cheng P, Celis E, Pisarev V, Sherman S, Sporn MB, Gabrilovich D (2011) Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J Clin Invest 121(10):4015–4029PubMedCrossRef

28.

Solito S, Falisi E, Diaz-Montero CM, Doni A, Pinton L, Rosato A, Francescato S, Basso G, Zanovello P, Onicescu G et al (2011) A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood 118(8):2254–2265PubMedCrossRef

29.

Lechner MG, Liebertz DJ, Epstein AL (2010) Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. J Immunol 185(4):2273–2284PubMedCrossRef

30.

Bruchard M, Mignot G, Derangere V, Chalmin F, Chevriaux A, Vegran F, Boireau W, Simon B, Ryffel B, Connat JL et al (2013) Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat Med 19(1):57–64PubMedCrossRef

31.

Lechner MG, Megiel C, Russell SM, Bingham B, Arger N, Woo T, Epstein AL (2011) Functional characterization of human Cd33+ and Cd11b+ myeloid-derived suppressor cell subsets induced from peripheral blood mononuclear cells co-cultured with a diverse set of human tumor cell lines. J Transl Med 9:90PubMedCrossRef

32.

Morales JK, Kmieciak M, Knutson KL, Bear HD, Manjili MH (2010) GM-CSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11b-Gr1- bone marrow progenitor cells into myeloid-derived suppressor cells. Breast Cancer Res Treat 123(1):39–49PubMedCrossRef

33.

Roland CL, Lynn KD, Toombs JE, Dineen SP, Udugamasooriya DG, Brekken RA (2009) Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer. PLoS One 4(11):e7669PubMedCrossRef

34.

Kerkar SP, Goldszmid RS, Muranski P, Chinnasamy D, Yu Z, Reger RN, Leonardi AJ, Morgan RA, Wang E, Marincola FM et al (2011) IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. J Clin Invest 121(12):4746–4757PubMedCrossRef

35.

Steding CE, Wu ST, Zhang Y, Jeng MH, Elzey BD, Kao C (2011) The role of interleukin-12 on modulating myeloid-derived suppressor cells, increasing overall survival and reducing metastasis. Immunology 133(2):221–238PubMedCrossRef

36.

Liu Y, Lai L, Chen Q, Song Y, Xu S, Ma F, Wang X, Wang J, Yu H, Cao X et al (2012) MicroRNA-494 is required for the accumulation and functions of tumor-expanded myeloid-derived suppressor cells via targeting of PTEN. J Immunol 188(11):5500–5510PubMedCrossRef

37.

Markowitz J, Carson WE 3rd (2013) Review of S100A9 biology and its role in cancer. Biochim Biophys Acta 1835(1):100–109PubMed

38.

Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM, Ortiz M, Nacken W, Sorg C, Vogl T et al (2008) Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 205(10):2235–2249PubMedCrossRef

39.

Sinha P, Okoro C, Foell D, Freeze HH, Ostrand-Rosenberg S, Srikrishna G (2008) Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J Immunol 181(7):4666–4675PubMed

40.

Morales JK, Kmieciak M, Graham L, Feldmesser M, Bear HD, Manjili MH (2009) Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells. Cancer Immunol Immunother 58(6):941–953PubMedCrossRef

41.

Thakur A, Schalk D, Sarkar SH, Al-Khadimi Z, Sarkar FH, Lum LG (2011) A Th1 cytokine-enriched microenvironment enhances tumor killing by activated T cells armed with bispecific antibodies and inhibits the development of myeloid-derived suppressor cells. Cancer Immunol Immunother 61(4):497–509PubMedCrossRef

42.

Walker JD, Sehgal I, Kousoulas KG (2011) Oncolytic herpes simplex virus 1 encoding 15-prostaglandin dehydrogenase mitigates immune suppression and reduces ectopic primary and metastatic breast cancer in mice. J Virol 85(14):7363–7371PubMedCrossRef

43.

Clynes RA, Towers TL, Presta LG, Ravetch JV (2000) Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med 6(4):443–446PubMedCrossRef

44.

Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H, Lehner F, Manns MP, Greten TF, Korangy F (2009) Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50(3):799–807PubMedCrossRef

45.

Li H, Han Y, Guo Q, Zhang M, Cao X (2009) Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol 182(1):240–249PubMed

46.

Melani C, Sangaletti S, Barazzetta FM, Werb Z, Colombo MP (2007) 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(23):11438–11446PubMedCrossRef

47.

Zhang Y, Lv D, Kim HJ, Kurt RA, Bu W, Li Y, Ma X (2013) A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells. Cell Res 23(3):394–408PubMedCrossRef

48.

Ugel S, Delpozzo F, Desantis G, Papalini F, Simonato F, Sonda N, Zilio S, Bronte V (2009) Therapeutic targeting of myeloid-derived suppressor cells. Curr Opin Pharmacol 9(4):470–481PubMedCrossRef

49.

Kusmartsev S, Nefedova Y, Yoder D, 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):989–999PubMed

50.

Nagaraj S, Schrum AG, Cho HI, Celis E, Gabrilovich DI (2010) Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J Immunol 184(6):3106–3116PubMedCrossRef

51.

Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, De Palma A, Mauri P, Monegal A, Rescigno M et al (2011) Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med 208(10):1949–1962PubMedCrossRef

52.

Mundy-Bosse BL, Thornton LM, Yang HC, Andersen BL, Carson WE (2011) Psychological stress is associated with altered levels of myeloid-derived suppressor cells in breast cancer patients. Cell Immunol 270(1):80–87PubMedCrossRef

Title: Myeloid-derived suppressor cells in breast cancer
Authors: Joseph Markowitz
Robert Wesolowski
Tracey Papenfuss
Taylor R. Brooks
William E. Carson III
Publication date: 01-07-2013
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2013
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-013-2618-7

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