Significance of myeloid-derived suppressor cells (MDSCs) like CD14+B7-H4 cells frequency in blood and tumor microcirculation of lung cancer patients

Jelena Vuković; Vukojica Karličić; Saša  Ristić; Ivan  Stanojević; Nevena Nikolić; Debra Štefik; Milena Jović; Džihan  Abazović; Gordana Supić; Danilo Vojvodić; Miloš  Pavlović

doi:10.2298/VSP190430106V

Jelena Vuković Military Medical Academy, Clinic for Pulmonology, Belgrade, Serbia
Vukojica Karličić Euromedik Special Hospital, Belgrade, Serbia
Saša Ristić Military Medical Academy, Institute of Pathology and Forensic Medicine, Belgrade, Serbia
Ivan Stanojević Military Medical Academy, Institute for Medical Research, Belgrade, Serbia
Nevena Nikolić University of Defence, Faculty of Medicine of the Military Medical Academy, Serbia, Belgrade
Debra Štefik Renova Center for Regenerative Medicine, Belgrade, Serbia
Milena Jović Euromedik Special Hospital, Belgrade, Serbia
Džihan Abazović Renova Center for Regenerative Medicine, Belgrade, Serbia
Gordana Supić Military Medical Academy, Institute for Medical Research, Belgrade, Serbia
Danilo Vojvodić Military Medical Academy, Institute for Medical Research, Belgrade, Serbia
Miloš Pavlović University of Belgrade, Faculty of Veterinary Medicine, Belgrade, Serbia

DOI: https://doi.org/10.2298/VSP190430106V

Keywords: lung neoplasms;, myeloid-derived suppressor cells;, immunologic factors;, neoplasm metastasis;, flow cytometry; histology.

Abstract

Background/Aim. Myeloid-derived suppressor cells (MDSCs) suppress immune responses via a series of inhibitory mechanisms, which ultimately could lead to tumor growth. B7-H4 expression is significantly associated with poor outcome and promotion of tumor cell proliferation, invasion and migration in patients with various cancers. Data concerning B7-H4 expression in lung cancers (LC), either on tumor or immunological cells, are still sporadic. The aim was to estimate and correlate the number of CD14⁺B7-H4⁺MDSCs in blood and lung tumor microcirculation with clinical stage, histology type of tumor, tumor node metastasis (TNM) stadium, nodal status and disease outspread. Methods. The study included 44 lung cancer patients (III and IV clinical stage) and 30 healthy controls. CD14⁺B7-H4⁺ MDSC number was estimated by flow cytometry in blood and tumor microcirculation samples of each patient. Results. CD14⁺B7-H4⁺MDSCs number was significantly higher in patients’ samples compared to controls. CD14⁺B7-H4⁺MDSC number was significantly increased in tumor compared to blood sample of the same patient. Clinical stage III patients had the increased number of the CD14⁺B7-H4⁺MDSC compared to stage IV, in both types of samples. According to histology, small cell lung cancer (SCLC) patients had the highest average CD14⁺B7-H4⁺MDSCs number, significantly increased compared to patients with squamous and large cell LC histology type. Tumor size was directly associated with the number of the CD14⁺B7-H4⁺MDSC, both in blood and tumor samples. Furthermore, nodal involvement was associated with the gradual increase of the CD14⁺B7-H4⁺MDSC number, being the highest in the N3 group, again both in blood and tumor samples. Finally, we detected higher CD14⁺B7-H4⁺MDSCs number in the samples of patients without metastases. Conclusion. CD14⁺B7-H4⁺MDSCs number in LC patients is significantly associated with tumor histology type, lymph node involvement, disease extent degree and tumor size. Concerning their large number in LC tumor microenvironment together with immunosuppressive capacities, CD14⁺B7-H4⁺MDSCs could represent important tumor promoting factor in LC pathophysiology.

Author Biography

Miloš Pavlović, University of Belgrade, Faculty of Veterinary Medicine, Belgrade, Serbia

Fakultet veterinarske medicine

Katedra za porodiljstvo, sterilitet i v.o.

vanredni profesor

References

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, еt al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136(5): E359‒86.

Ni L, Dong C. New B7 family checkpoints in human cancers. Mol Cancer Ther 2017; 16(7): 1203–11.

Sica GL, Choi IH, Zhu G, Tamada K, Wang SD, Tamura H, et al. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity 2003; 18(6): 849‒61.

Prasad DV, Richards S, Mai XM, Dong C. B7S1, a novel B7 family member that negatively regulates T cell activation. Immunity 2003; 18(6): 863‒73.

Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P, et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med 2006; 203(4): 871‒81.

Kryczek I, Wei S, Zhu G, Myers L, Mottram P, Cheng P, et al. Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Cancer Res 2007; 67(18): 8900‒5.

Yao Y, Ye H, Qi Z, Mo L, Yue Q, Baral A, et al. B7-H4(B7x)-mediated cross-talk between glioma-initiating cells and macrophages via the IL6/JAK/STAT3 pathway lead to poor prognosis in glioma patients. Clin Cancer Res 2016; 22(11): 2778‒90.

Li J, Lee Y, Li Y, Jiang Y, Lu H, Zang W, et al. Co-inhibitory molecule B7 superfamily member 1 expressed by tumor-infiltrating myeloid cells induces dysfunction of anti-tumor CD8+ T cells. Immunity 2018; 48(4): 773‒86. e5.

Ortiz ML, Lu L, Ramachandran I, Gabrilovich I. Myeloid-derived suppressor cells in the development of lung cancer. Cancer Immunol Res 2014; 2(1): 50‒8.

Weber R, Fleming V, Hu X, Nagibin V, Groth C, Altevogt P, et al. Myeloid-derived suppressor cells hinder the anti-cancer activity of immune checkpoint inhibitors. Front Immunol 2018; 9: 1310.

Yamauchi Y, Safi S, Blattner C, Rathinasamy A, Umansky L, Juenger S, et al. Circulating and Tumor Myeloid-derived Suppressor Cells in Resectable Non–Small Cell Lung Cancer. Am J Respir Crit Care Med 2018; 198(6): 777‒87.

Zhang G, Huang H, Zhu Y, Yu G, Gao X, Xu Y, et al. A novel subset of B7-H3+CD14+HLA-DR-/low myeloid-derived suppressor cells are associated with progression of human NSCLC. Oncoimmunology 2015; 4(2): e977164.

Stanojevic I, Miller K, Kandolf-Sekulovic L, Mijuskovic Z, Zolotarevski Z, Jovic M, et al. A subpopulation that may correspond to granulocytic myeloid-derived suppressor cells reflects the clinical stage and progression of cutaneous melanoma. Int Immunol 2016; 28(2): 87‒97.

Simon I, Katsaros D, Rigault de la Longrais I, Massobrio M, Scorilas A, Kim NW et al. B7-H4 is over-expressed in early - stage ovarian cancer and is independent of CA-125 expression. Gynecol Oncol 2007; 106(2): 334‒41.

Qian Y, Shen L, Cheng L, Wu Z, Yao H. B7-H4 expression in various tumors determined using a novel developed monoclonal antibody. Clin Exp Med 2011; 11(3): 163‒70.

Choi IH, Zhu G, Sica GL, Strome SE, Cheville JC, Lau JS, et al. Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family. J Immunol 2003; 171(9): 4650‒4.

Dangaj D, Lanitis E, Zhao A, Joshi S, Cheng Y, Sandaltzopoulos R, et al. Novel recombinant human B7-H4 antibodies overcome tumoral immune escape to potentiate T cell anti-tumor responses. Cancer Res 2013; 73(15): 4820‒9.

Kryczek I, Wei S, Zou L, Zhu G, Mottram P, Xu H, et al. Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells. J Immunol 2006; 177(1): 40–4.

Matsunaga T, Saito H, Ikeguchi M. Increased B7-H1 and B7-H4 Expressions on Circulating Monocytes and Tumor-Associated Macrophages are Involved in Immune Evasion in Patients with Gastric Cancer. Yonago Acta Med 2011; 54(1): 1‒10.

Tan Z, Shen W. Prognostic role of B7-H4 in patients with non-small cell lung cancer: A meta-analysis. Oncotarget 2017; 8(16): 27137‒44.

Chen Y, Pan G, Tian D, Zhang Y, Li T. Functional analysis of CD14+HLADR/low myeloid-derived suppressor cells in patients with lung squamous cell carcinoma. Oncol Lett 2017; 14(1): 349‒54.

Schneider T, Hoffmann H, Dienemann H, Schnabel PA, Enk AH, Ring S, et al. Non-small cell lung cancer induces an immunosuppressive phenotype of dendritic cells in tumor microenvironment by upregulating B7-H3. J Thorac Oncol 2011; 6(7): 1162‒8.

Huang A, Zhang B, Wang B, Zhang F, Fan KX, Guo Y. 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 2013; 62(9): 1439‒51.

Hamilton G, Rath B, Klameth L, Hochmair MJ. Small cell lung cancer: Recruitment of macrophages by circulating tumor cells. Oncoimmunology 2015; 5(3): e1093277.

Feng PH, Yu CT, Chen KY, Luo CS, Wu SM, Liu CY, et al. S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB. Oncotarget 2018; 9(7): 7631‒43.

Karlicic V, Vukovic J, Stanojevic I, Sotirovic J, Peric A, Jovic M, et al. Association of locally produced IL10 and TGFb1 with tumor size, histological type and presence of metastases in patients with lung carcinoma. J BUON 2016; 21(5): 1210‒8.

Pogoda K, Pyszniak M, Rybojad P, Tabarkiewicz J. Monocytic myeloid-derived suppressor cells as a potent suppressor of tumor immunity in non-small cell lung cancer. Oncol Lett 2016; 12(6): 4785–94.

Heuvers ME, Muskens F, Bezemer K, Lambers M, Dingemans AM, Groen HJ, et al. Arginase-1 mRNA expression correlates with myeloid-derived suppressor cell levels in peripheral blood of NSCLC patients. Lung Cancer 2013; 81(3): 468‒74.

Tian T, Gu X, Zhang B, Liu Y, Yuan C, Shao L, et al. Increased circulating CD14(+) HLA-DR-/low myeloid-derived suppressor cells are associated with poor prognosis in patients with small-cell lung cancer. Cancer Biomark 2015; 15(4): 425‒32.