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Breast Cancer Research
Published in: Breast Cancer Research 1/2019

Open Access 01-12-2019 | Metastasis | Research article

Targeting myeloid-derived suppressor cells in combination with primary mammary tumor resection reduces metastatic growth in the lungs

Authors: Momir Bosiljcic, Rachel A. Cederberg, Melisa J. Hamilton, Nancy E. LePard, Bryant T. Harbourne, Jenna L. Collier, Elizabeth C. Halvorsen, Rocky Shi, S. Elizabeth Franks, Ada Y. Kim, Judit P. Banáth, Mark Hamer, Fabio M. Rossi, Kevin L. Bennewith

Published in: Breast Cancer Research | Issue 1/2019

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Abstract

Background

Solid tumors produce proteins that can induce the accumulation of bone marrow-derived cells in various tissues, and these cells can enhance metastatic tumor growth by several mechanisms. 4T1 murine mammary tumors are known to produce granulocyte colony-stimulating factor (G-CSF) and increase the numbers of immunosuppressive CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) in tissues such as the spleen and lungs of tumor-bearing mice. While surgical resection of primary tumors decreases MDSC levels in the spleen, the longevity and impact of MDSCs and other immune cells in the lungs after tumor resection have been less studied.

Methods

We used mass cytometry time of flight (CyTOF) and flow cytometry to quantify MDSCs in the spleen, peripheral blood, and lungs of mice bearing orthotopic murine mammary tumors. We also tested the effect of primary tumor resection and/or gemcitabine treatment on the levels of MDSCs, other immune suppressor and effector cells, and metastatic tumor cells in the lungs.

Results

We have found that, similar to mice with 4T1 tumors, mice bearing metastatic 4T07 tumors also exhibit accumulation of CD11b+Gr1+ MDSCs in the spleen and lungs, while tissues of mice with non-metastatic 67NR tumors do not contain MDSCs. Mice with orthotopically implanted 4T1 tumors have increased granulocytic (G-) MDSCs, monocytic (M-) MDSCs, macrophages, eosinophils, and NK cells in the lungs. Resection of primary 4T1 tumors decreases G-MDSCs, M-MDSCs, and macrophages in the lungs within 48 h, but significant numbers of functional immunosuppressive G-MDSCs persist in the lungs for 2 weeks after tumor resection, indicative of an environment that can promote metastatic tumor growth. The chemotherapeutic agent gemcitabine depletes G-MDSCs, M-MDSCs, macrophages, and eosinophils in the lungs of 4T1 tumor-bearing mice, and we found that treating mice with gemcitabine after primary tumor resection decreases residual G-MDSCs in the lungs and decreases subsequent metastatic growth.

Conclusions

Our data support the development of therapeutic strategies to target MDSCs and to monitor MDSC levels before and after primary tumor resection to enhance the effectiveness of immune-based therapies and improve the treatment of metastatic breast cancer in the clinic.
Appendix
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Literature
1.
2.
Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med. 2006;12(8):895–904.PubMedCrossRef
3.
Paget S. The distribution of secondary growths in cancer of the breast. Cancer Metastasis Rev. 1989;8(2):98–101.PubMed
4.
Bennewith KL, Erler JT, Giaccia AJ. Pre-metastatic niches. In: Siemann DW, editor. Tumor microenvironment. 1st ed. Chichester: Wiley; 2011. p. 161–82.
5.
Sceneay J, Smyth MJ, Moller A. The pre-metastatic niche: finding common ground. Cancer Metastasis Rev. 2013;32(3–4):449–64.PubMedCrossRef
6.
Sceneay J, Chow MT, Chen A, Halse HM, Wong CS, Andrews DM, et al. Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res. 2012;72(16):3906–11.PubMedCrossRef
7.
Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell. 2009;15(1):35–44.PubMedPubMedCentralCrossRef
8.
Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005;438(7069):820–7.PubMedPubMedCentralCrossRef
9.
Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012;18(6):883–91.PubMedPubMedCentralCrossRef
10.
Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med. 2013;91(4):431–7.PubMedCrossRef
11.
12.
Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, et al. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell. 2008;13(1):23–35.PubMedPubMedCentralCrossRef
13.
Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E, et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell. 2008;13(3):206–20.PubMedPubMedCentralCrossRef
14.
De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell. 2005;8(3):211–26.PubMedCrossRef
15.
Shojaei F, Ferrara N. Refractoriness to antivascular endothelial growth factor treatment: role of myeloid cells. Cancer Res. 2008;68(14):5501–4.PubMedCrossRef
16.
Ahn GO, Brown JM. Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell. 2008;13(3):193–205.PubMedPubMedCentralCrossRef
17.
Kowanetz M, Wu X, Lee J, Tan M, Hagenbeek T, Qu X, et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes. Proc Natl Acad Sci U S A. 2010;107(50):21248–55.PubMedPubMedCentralCrossRef
18.
Chafe SC, Lou Y, Sceneay J, Vallejo M, Hamilton MJ, McDonald PC, et al. Carbonic anhydrase IX promotes myeloid-derived suppressor cell mobilization and establishment of a metastatic niche by stimulating G-CSF production. Cancer Res. 2015;75(6):996–1008.PubMedCrossRef
19.
Oh K, Lee OY, Shon SY, Nam O, Ryu PM, Seo MW, et al. A mutual activation loop between breast cancer cells and myeloid-derived suppressor cells facilitates spontaneous metastasis through IL-6 trans-signaling in a murine model. Breast Cancer Res. 2013;15(5):R79.PubMedPubMedCentralCrossRef
20.
DuPre SA, Redelman D, Hunter KW Jr. The mouse mammary carcinoma 4T1: characterization of the cellular landscape of primary tumours and metastatic tumour foci. Int J Exp Pathol. 2007;88(5):351–60.PubMedPubMedCentralCrossRef
21.
22.
Youn JI, Gabrilovich DI. The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol. 2010;40(11):2969–75.PubMedPubMedCentralCrossRef
23.
Liu C, Yu S, Kappes J, Wang J, Grizzle WE, Zinn KR, et al. Expansion of spleen myeloid suppressor cells represses NK cell cytotoxicity in tumor-bearing host. Blood. 2007;109(10):4336–42.PubMedPubMedCentralCrossRef
24.
Drews-Elger K, Iorns E, Dias A, Miller P, Ward TM, Dean S, et al. Infiltrating S100A8+ myeloid cells promote metastatic spread of human breast cancer and predict poor clinical outcome. Breast Cancer Res Treat. 2014;148(1):41–59.PubMedCrossRef
25.
Nagaraj S, Gabrilovich DI. Myeloid-derived suppressor cells in human cancer. Cancer J. 2010;16(4):348–53.PubMedCrossRef
26.
Movahedi K, Guilliams M, Van den Bossche J, Van den Bergh R, Gysemans C, Beschin A, et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood. 2008;111(8):4233–44.PubMedCrossRef
27.
28.
Mirza N, Fishman M, Fricke I, Dunn M, Neuger AM, Frost TJ, et al. All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res. 2006;66(18):9299–307.PubMedPubMedCentralCrossRef
29.
Kusmartsev S, Su Z, Heiser A, Dannull J, Eruslanov E, Kubler H, et al. Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma. Clin Cancer Res. 2008;14(24):8270–8.PubMedCrossRef
30.
Lathers DM, Clark JI, Achille NJ, Young MR. Phase 1B study to improve immune responses in head and neck cancer patients using escalating doses of 25-hydroxyvitamin D3. Cancer Immunol Immunother. 2004;53(5):422–30.PubMedCrossRef
31.
Sinha P, Clements VK, Ostrand-Rosenberg S. Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease. J Immunol. 2005;174(2):636–45.PubMedCrossRef
32.
Ghochikyan A, Davtyan A, Hovakimyan A, Davtyan H, Poghosyan A, Bagaev A, et al. Primary 4T1 tumor resection provides critical “window of opportunity” for immunotherapy. Clin Exp Metastasis. 2014;31(2):185–98.PubMedCrossRef
33.
Aslakson CJ, Miller FR. Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res. 1992;52(6):1399–405.PubMed
34.
Hamilton MJ, Banath JP, Lam V, Lepard NE, Krystal G, Bennewith KL. Serum inhibits the immunosuppressive function of myeloid-derived suppressor cells isolated from 4T1 tumor-bearing mice. Cancer Immunol Immunother. 2012;61(5):643–54.PubMedCrossRef
35.
Hamilton MJ, Bosiljcic M, Lepard NE, Halvorsen EC, Ho VW, Banath JP, et al. Macrophages are more potent immune suppressors ex vivo than immature myeloid-derived suppressor cells induced by metastatic murine mammary carcinomas. J Immunol. 2014;192(1):512–22.PubMedCrossRef
36.
Finck R, Simonds EF, Jager A, Krishnaswamy S, Sachs K, Fantl W, et al. Normalization of mass cytometry data with bead standards. Cytometry A. 2013;83(5):483–94.PubMedPubMedCentralCrossRef
37.
Fread KI, Strickland WD, Nolan GP, Zunder ER. An updated debarcoding tool for mass cytometry with cell type-specific and cell sample-specific stringency adjustment. Pac Symp Biocomput. 2016;22:588–98.
38.
DuPre SA, Hunter KW Jr. Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: association with tumor-derived growth factors. Exp Mol Pathol. 2007;82(1):12–24.PubMedCrossRef
39.
Bosiljcic M, Hamilton MJ, Banath JP, Lepard NE, McDougal DC, Jia JX, et al. Myeloid suppressor cells regulate the lung environment--letter. Cancer Res. 2011;71(14):5050–1 author reply 2-3.PubMedCrossRef
40.
Gambotto A, Dworacki G, Cicinnati V, Kenniston T, Steitz J, Tuting T, et al. Immunogenicity of enhanced green fluorescent protein (EGFP) in BALB/c mice: identification of an H2-Kd-restricted CTL epitope. Gene Ther. 2000;7(23):2036–40.PubMedCrossRef
41.
Steinbauer M, Guba M, Cernaianu G, Kohl G, Cetto M, Kunz-Schughart LA, et al. GFP-transfected tumor cells are useful in examining early metastasis in vivo, but immune reaction precludes long-term tumor development studies in immunocompetent mice. Clin Exp Metastasis. 2003;20(2):135–41.PubMedCrossRef
42.
Stripecke R, Carmen Villacres M, Skelton D, Satake N, Halene S, Kohn D. Immune response to green fluorescent protein: implications for gene therapy. Gene Ther. 1999;6(7):1305–12.PubMedCrossRef
43.
Condamine T, Kumar V, Ramachandran IR, Youn JI, Celis E, Finnberg N, et al. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J Clin Invest. 2014;124(6):2626–39.PubMedPubMedCentralCrossRef
44.
Czuprynski CJ, Brown JF, Maroushek N, Wagner RD, Steinberg H. Administration of anti-granulocyte mAb RB6-8C5 impairs the resistance of mice to listeria monocytogenes infection. J Immunol. 1994;152(4):1836–46.PubMed
45.
Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res. 2005;11(18):6713–21.PubMedCrossRef
46.
Suzuki E, Sun J, Kapoor V, Jassar AS, Albelda SM. Gemcitabine has significant immunomodulatory activity in murine tumor models independent of its cytotoxic effects. Cancer Biol Ther. 2007;6(6):880–5.PubMedCrossRef
47.
Apolloni E, Bronte V, Mazzoni A, Serafini P, Cabrelle A, Segal DM, et al. Immortalized myeloid suppressor cells trigger apoptosis in antigen-activated T lymphocytes. J Immunol. 2000;165(12):6723–30.PubMedCrossRef
48.
Ikutani M, Yanagibashi T, Ogasawara M, Tsuneyama K, Yamamoto S, Hattori Y, et al. Identification of innate IL-5-producing cells and their role in lung eosinophil regulation and antitumor immunity. J Immunol. 2012;188(2):703–13.PubMedCrossRef
49.
Boutte AM, McDonald WH, Shyr Y, Yang L, Lin PC. Characterization of the MDSC proteome associated with metastatic murine mammary tumors using label-free mass spectrometry and shotgun proteomics. PLoS One. 2011;6(8):e22446.PubMedPubMedCentralCrossRef
50.
Quail DF, Olson OC, Bhardwaj P, Walsh LA, Akkari L, Quick ML, et al. Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF. Nat Cell Biol. 2017;19(8):974–87.PubMedPubMedCentralCrossRef
51.
Waight JD, Hu Q, Miller A, Liu S, Abrams SI. Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism. PLoS One. 2011;6(11):e27690.PubMedPubMedCentralCrossRef
52.
Halvorsen EC, Franks SE, Wadsworth BJ, Harbourne BT, Cederberg RA, Steer CA, et al. IL-33 increases ST2(+) Tregs and promotes metastatic tumour growth in the lungs in an amphiregulin-dependent manner. Oncoimmunology. 2019;8(2):e1527497.PubMedCrossRef
53.
Stolarski B, Kurowska-Stolarska M, Kewin P, Xu D, Liew FY. IL-33 exacerbates eosinophil-mediated airway inflammation. J Immunol. 2010;185(6):3472–80.PubMedCrossRef
54.
Tai LH, Alkayyal AA, Leslie AL, Sahi S, Bennett S, Tanese de Souza C, et al. Phosphodiesterase-5 inhibition reduces postoperative metastatic disease by targeting surgery-induced myeloid derived suppressor cell-dependent inhibition of natural killer cell cytotoxicity. Oncoimmunology. 2018;7(6):e1431082.PubMedPubMedCentralCrossRef
55.
Tai LH, Tanese de Souza C, Sahi S, Zhang J, Alkayyal AA, Ananth AA, et al. A mouse tumor model of surgical stress to explore the mechanisms of postoperative immunosuppression and evaluate novel perioperative immunotherapies. J Vis Exp. 2014;(85):e51253.
56.
Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother. 2009;58(1):49–59.PubMedCrossRef
57.
Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW. Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother. 2011;60(10):1419–30.PubMedPubMedCentralCrossRef
58.
Solito S, Falisi E, Diaz-Montero CM, Doni A, Pinton L, Rosato A, et al. A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood. 2011;118(8):2254–65.PubMedPubMedCentralCrossRef
59.
Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res. 2009;15(6):2148–57.PubMedCrossRef
60.
Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med. 2006;203(12):2691–702.PubMedPubMedCentralCrossRef
61.
Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, et al. 5-fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 2010;70(8):3052–61.PubMedCrossRef
62.
Le HK, Graham L, Cha E, Morales JK, Manjili MH, Bear HD. 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. 2009;9(7–8):900–9.PubMedCrossRef
63.
Eriksson E, Wenthe J, Irenaeus S, Loskog A, Ullenhag G. Gemcitabine reduces MDSCs, tregs and TGFbeta-1 while restoring the teff/treg ratio in patients with pancreatic cancer. J Transl Med. 2016;14(1):282.PubMedPubMedCentralCrossRef
64.
Gebremeskel S, Lobert L, Tanner K, Walker B, Oliphant T, Clarke LE, et al. Natural killer T-cell immunotherapy in combination with chemotherapy-induced immunogenic cell death targets metastatic breast cancer. Cancer Immunol Res. 2017;5(12):1086–97.PubMedCrossRef
Metadata
Title
Targeting myeloid-derived suppressor cells in combination with primary mammary tumor resection reduces metastatic growth in the lungs
Authors
Momir Bosiljcic
Rachel A. Cederberg
Melisa J. Hamilton
Nancy E. LePard
Bryant T. Harbourne
Jenna L. Collier
Elizabeth C. Halvorsen
Rocky Shi
S. Elizabeth Franks
Ada Y. Kim
Judit P. Banáth
Mark Hamer
Fabio M. Rossi
Kevin L. Bennewith
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2019
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-019-1189-x

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