Monocytic myeloid-derived suppressor cells as a potent suppressor of tumor immunity in non-small cell lung cancer

Pogoda,Katarzyna; Pyszniak,Maria; Rybojad,Paweł; Tabarkiewicz,Jacek

doi:10.3892/ol.2016.5273

Monocytic myeloid-derived suppressor cells as a potent suppressor of tumor immunity in non-small cell lung cancer

Authors:
- Katarzyna Pogoda
- Maria Pyszniak
- Paweł Rybojad
- Jacek Tabarkiewicz
View Affiliations

Affiliations: Centre for Innovative Research in Medical and Natural Sciences, Faculty of Medicine, University of Rzeszow, 35‑310 Rzeszow, Poland, Department of Thoracic Surgery, Medical University of Lublin, 20‑097 Lublin, Poland
Published online on: October 18, 2016 https://doi.org/10.3892/ol.2016.5273
Pages: 4785-4794

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Immunotherapy is a promising therapeutic option for patients with non-small cell lung cancer (NSCLC) who do not qualify for surgery. In patients with advanced NSCLC, systemic immune suppression is frequently observed, therefore, researchers are investigating the tumor microenvironment for less invasive and more effective methods of treating lung cancer. Monocytic myeloid‑derived suppressor cells (Mo‑MDSCs) are potent suppressors of tumor immunity; therefore, this population may significantly impede the application of immunotherapy to treat cancer. The present study evaluated the distribution of Mo‑MDSCs and monocytes/macrophages in the peripheral blood, lymph nodes and tumor tissue of patients with NSCLC. Furthermore, the profiles of cytokines produced by these cell populations, including interleukin (IL)‑1β, IL‑12/23p40, IL‑10, transforming growth factor‑β (TGF‑β) and tumor necrosis factor (TNF), were compared. The cell populations and the expression of cytokines were assessed by flow cytometry after 4 h in culture with mitogens and Brefeldin A. Mo‑MDSCs were more numerous than monocytes/macrophages in all tissues and their prevalence was highest in the peripheral blood; they expressed higher levels of TGF‑β than monocytes/macrophages in all tissues and expression of TGF‑β produced by Mo‑MDSCs was higher in the blood than in lymph nodes and tumor tissues. A higher percentage of monocytes/macrophages was observed in lymph nodes and tumor tissues than in blood. CD14+HLA‑DR+ cells also produced more IL‑10 in lymph nodes than Mo‑MDSCs and more IL‑1β and TNF in all tissues. A higher prevalence of cluster of differentiation 14+ human leukocyte antigen‑D related+ cells secreting IL‑1β, TNF and IL‑12/23p40 was observed in peripheral blood. Thus, the results of the current study support the statement that Mo‑MDSCs and monocytes/macrophages participate in NSCLC induced immunosuppression, and is consistent with previous research into associations between the TGF‑β signaling pathway and tumor cell invasion, motility and metastasis. The study also demonstrated that Mo‑MDSCs promote tumor growth through their immunosuppressive activity. In addition, the profile of cytokines expressed by monocytes/macrophages suggests that this cell population may be associated with metastasis formation and angiogenesis promotion in patients with NSCLC.

View Figures

View References

1	Nur U, Quaresma M, De Stavola B, Peake M and Rachet B: Inequalities in non-small cell lung cancer treatment and mortality. J Epidemiol Community Health. 69:985–992. 2015. View Article : Google Scholar : PubMed/NCBI
2	Thomas A, Chen Y, Yu T, Jakopovic M and Giaccone G: Trends and characteristics of young non-small cell lung cancer patients in the United States. Front Oncol. 5:1132015. View Article : Google Scholar : PubMed/NCBI
3	Aerts JG, Lievense LA, Hoogsteden HC and Hegmans JP: Immunotherapy prospects in the treatment of lung cancer and mesothelioma. Transl Lung Cancer Res. 3:34–45. 2014.PubMed/NCBI
4	Ohki S, Shibata M, Gonda K, Machida T, Shimura T, Nakamura I, Ohtake T, Koyama Y, Suzuki S, Ohto H and Takenoshita S: Circulating myeloid-derived suppressor cells are increased and correlate to immune suppression, inflammation and hypoproteinemia in patients with cancer. Oncol Rep. 28:453–458. 2012.PubMed/NCBI
5	Huang A, Zhang B, Wang B, Zhang F, Fan KX and Guo YJ: Increased CD14(+)HLA-DR (−/low) myeloid-derived suppressor cells correlate with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer patients. Cancer Immunol Immunother. 62:1439–1451. 2013. View Article : Google Scholar : PubMed/NCBI
6	Ostrand-Rosenberg S: Myeloid-derived suppressor cells: More mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother. 59:1593–1600. 2010. View Article : Google Scholar : PubMed/NCBI
7	Parker KH, Beury DW and Ostrand-Rosenberg S: Myeloid-Derived suppressor cells: Critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res. 128:95–139. 2015. View Article : Google Scholar : PubMed/NCBI
8	Marigo I, Dolcetti L, Serafini P, Zanovello P and Bronte V: Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev. 222:162–179. 2008. View Article : Google Scholar : PubMed/NCBI
9	Damuzzo V, Pinton L, Desantis G, Solito S, Marigo I, Bronte V and Mandruzzato S: Complexity and challenges in defining myeloid-derived suppressor cells. Cytometry B Clin Cytom. 88:77–91. 2015. View Article : Google Scholar : PubMed/NCBI
10	Ortiz ML, Lu L, Ramachandran I and Gabrilovich DI: Myeloid-derived suppressor cells in the development of lung cancer. Cancer Immunol Res. 2:50–58. 2014. View Article : Google Scholar : PubMed/NCBI
11	Dolcetti L, Peranzoni E, Ugel S, Marigo I, Gomez A Fernandez, Mesa C, Geilich M, Winkels G, Traggiai E, Casati A, et al: Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol. 40:22–35. 2010. View Article : Google Scholar : PubMed/NCBI
12	Fujimura T, Mahnke K and Enk AH: Myeloid derived suppressor cells and their role in tolerance induction in cancer. J Dermatol Sci. 59:1–6. 2010. View Article : Google Scholar : PubMed/NCBI
13	Qu P, Wang LZ and Lin PC: Expansion and functions of myeloid-derived suppressor cells in the tumor microenvironment. Cancer Lett. 380:253–256. 2016. View Article : Google Scholar : PubMed/NCBI
14	Schilling B, Sucker A, Griewank K, Zhao F, Weide B, Görgens A, Giebel B, Schadendorf D and Paschen A: Vemurafenib reverses immunosuppression by myeloid derived suppressor cells. Int J Cancer. 133:1653–1663. 2013. View Article : Google Scholar : PubMed/NCBI
15	Vetsika EK, Koinis F, Gioulbasani M, Aggouraki D, Koutoulaki A, Skalidaki E, Mavroudis D, Georgoulias V and Kotsakis A: A circulating subpopulation of monocytic myeloid-derived suppressor cells as an independent prognostic/predictive factor in untreated non-small lung cancer patients. J Immunol Res. 2014:6592942014. View Article : Google Scholar : PubMed/NCBI
16	Schmid MC and Varner JA: Myeloid cells in the tumor microenvironment: Modulation of tumor angiogenesis and tumor inflammation. J Oncol. 2010:2010262010. View Article : Google Scholar : PubMed/NCBI
17	Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S and Bronte V: Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci. 1319:47–65. 2014. View Article : Google Scholar : PubMed/NCBI
18	Mandruzzato S, Solito S, Falisi E, Francescato S, Chiarion-Sileni V, Mocellin S, Zanon A, Rossi CR, Nitti D, Bronte V and Zanovello P: IL4Ralpha+ myeloid-derived suppressor cell expansion in cancer patients. J Immunol. 182:6562–6568. 2009. View Article : Google Scholar : PubMed/NCBI
19	Mirsadraee S, Oswal D, Alizadeh Y, Caulo A and van Beek E Jr: The 7th lung cancer TNM classification and staging system: Review of the changes and implications. World J Radiol. 4:128–134. 2012. View Article : Google Scholar : PubMed/NCBI
20	Ridge CA, McErlean AM and Ginsberg MS: Epidemiology of lung cancer. Semin Intervent Radiol. 30:93–98. 2013. View Article : Google Scholar : PubMed/NCBI
21	Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, Lichtor T, Decker WK, Whelan RL, Kumara HM, et al: Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin Cancer Biol. 35:(Suppl). S185–S198. 2015. View Article : Google Scholar : PubMed/NCBI
22	Parcesepe P, Giordano G, Laudanna C, Febbraro A and Pancione M: Cancer-associated immune resistance and evasion of immune surveillance in colorectal cancer. Gastroenterol Res Pract. 2016:62617212016. View Article : Google Scholar : PubMed/NCBI
23	Curiel TJ: Regulatory T cells and treatment of cancer. Curr Opin Immunol. 20:241–246. 2008. View Article : Google Scholar : PubMed/NCBI
24	Stewart TJ and Abrams SI: How tumours escape mass destruction. Oncogene. 27:5894–5903. 2008. View Article : Google Scholar : PubMed/NCBI
25	Berzofsky JA and Terabe M: NKT cells in tumor immunity: Opposing subsets define a new immunoregulatory axis. J Immunol. 180:3627–3635. 2008. View Article : Google Scholar : PubMed/NCBI
26	Marvel D and Gabrilovich DI: Myeloid-derived suppressor cells in the tumor microenvironment: Expect the unexpected. J Clin Invest. 125:3356–3364. 2015. View Article : Google Scholar : PubMed/NCBI
27	Adams JL, Smothers J, Srinivasan R and Hoos A: Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov. 14:603–622. 2015. View Article : Google Scholar : PubMed/NCBI
28	Mahoney KM, Rennert PD and Freeman GJ: Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov. 14:561–584. 2015. View Article : Google Scholar : PubMed/NCBI
29	Sinha P and Ostrand-Rosenberg S: Myeloid-derived suppressor cell function is reduced by Withaferin A, a potent and abundant component of Withania somnifera root extract. Cancer Immunol Immunother. 62:1663–1673. 2013. View Article : Google Scholar : PubMed/NCBI
30	Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rébé C and Ghiringhelli F: 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 70:3052–3061. 2010. View Article : Google Scholar : PubMed/NCBI
31	Yang WC, Ma G, Chen SH and Pan PY: Polarization and reprogramming of myeloid-derived suppressor cells. J Mol Cell Biol. 5:207–209. 2013. View Article : Google Scholar : PubMed/NCBI
32	Feng PH, Lee KY, Chang YL, Chan YF, Kuo LW, Lin TY, Chung FT, Kuo CS, Yu CT, Lin SM, et al: CD14(+)S100A9(+) monocytic myeloid-derived suppressor cells and their clinical relevance in non-small cell lung cancer. Am J Respir Crit Care Med. 186:1025–1036. 2012. View Article : Google Scholar : PubMed/NCBI
33	De Keersmaecker B, Fostier K, Corthals J, Wilgenhof S, Heirman C, Aerts JL, Thielemans K and Schots R: Immunomodulatory drugs improve the immune environment for dendritic cell-based immunotherapy in multiple myeloma patients after autologous stem cell transplantation. Cancer Immunol Immunother. 63:1023–1036. 2014. View Article : Google Scholar : PubMed/NCBI
34	Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, Cho HI, Celis E, Quiceno DG, Padhya T, et al: HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 207:2439–2453. 2010. View Article : Google Scholar : PubMed/NCBI
35	Kumar V and Gabrilovich DI: Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment. Immunology. 143:512–519. 2014. View Article : Google Scholar : PubMed/NCBI
36	Krstic J and Santibanez JF: Transforming growth factor-beta and matrix metalloproteinases: Functional interactions in tumor stroma-infiltrating myeloid cells. Scientific World Journal. 2014:5217542014. View Article : Google Scholar : PubMed/NCBI
37	Beury DW, Parker KH, Nyandjo M, Sinha P, Carter KA and Ostrand-Rosenberg S: Cross-talk among myeloid-derived suppressor cells, macrophages, and tumor cells impacts the inflammatory milieu of solid tumors. J Leukoc Biol. 96:1109–1118. 2014. View Article : Google Scholar : PubMed/NCBI
38	O'Garra A, Barrat FJ, Castro AG, Vicari A and Hawrylowicz C: Strategies for use of IL-10 or its antagonists in human disease. Immunol Rev. 223:114–131. 2008. View Article : Google Scholar : PubMed/NCBI
39	Eruslanov E, Neuberger M, Daurkin I, Perrin GQ, Algood C, Dahm P, Rosser C, Vieweg J, Gilbert SM and Kusmartsev S: Circulating and tumor-infiltrating myeloid cell subsets in patients with bladder cancer. Int J Cancer. 130:1109–1119. 2012. View Article : Google Scholar : PubMed/NCBI
40	Xiu B, Lin Y, Grote DM, Ziesmer SC, Gustafson MP, Maas ML, Zhang Z, Dietz AB, Porrata LF, Novak AJ, et al: IL-10 induces the development of immunosuppressive CD14(+)HLA-DR (low/-) monocytes in B-cell non-Hodgkin lymphoma. Blood Cancer J. 5:e3282015. View Article : Google Scholar : PubMed/NCBI
41	Wang R, Lu M, Zhang J, Chen S, Luo X, Qin Y and Chen H: Increased IL-10 mRNA expression in tumor-associated macrophage correlated with late stage of lung cancer. J Exp Clin Cancer Res. 30:622011. View Article : Google Scholar : PubMed/NCBI
42	Lievense LA, Bezemer K, Aerts JG and Hegmans JP: Tumor-associated macrophages in thoracic malignancies. Lung Cancer. 80:256–262. 2013. View Article : Google Scholar : PubMed/NCBI
43	Zeni E, Mazzetti L, Miotto D, Lo Cascio N, Maestrelli P, Querzoli P, Pedriali M, De Rosa E, Fabbri LM, Mapp CE and Boschetto P: Macrophage expression of interleukin-10 is a prognostic factor in nonsmall cell lung cancer. Eur Respir J. 30:627–632. 2007. View Article : Google Scholar : PubMed/NCBI
44	Wesolowski R, Markowitz J and Carson WE III: Myeloid derived suppressor cells-a new therapeutic target in the treatment of cancer. J Immunother Cancer. 1:102013. View Article : Google Scholar : PubMed/NCBI
45	Quatromoni JG and Eruslanov E: Tumor-associated macrophages: Function, phenotype, and link to prognosis in human lung cancer. Am J Transl Res. 4:376–389. 2012.PubMed/NCBI
46	Ngiow SF, Teng MW and Smyth MJ: A balance of interleukin-12 and −23 in cancer. Trends Immunol. 34:548–555. 2013. View Article : Google Scholar : PubMed/NCBI
47	Ostrand-Rosenberg S, Sinha P, Beury DW and Clements VK: Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages and dendritic cells enhances tumor-induced immune suppression. Semin Cancer Biol. 22:275–281. 2012. View Article : Google Scholar : PubMed/NCBI
48	Baird AM, Leonard J, Naicker KM, Kilmartin L, O'Byrne KJ and Gray SG: IL-23 is pro-proliferative, epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer. Lung Cancer. 79:83–90. 2013. View Article : Google Scholar : PubMed/NCBI