Myeloid‑derived suppressor cells enhance the expression of melanoma‑associated antigen A4 in a Lewis lung cancer murine model

Shi,Guilan; Wang,Huiru; Zhuang,Xiufen

doi:10.3892/ol.2015.3918

Myeloid‑derived suppressor cells enhance the expression of melanoma‑associated antigen A4 in a Lewis lung cancer murine model

Authors:
- Guilan Shi
- Huiru Wang
- Xiufen Zhuang
View Affiliations

Affiliations: Department of Immunology, Zibo Vocational Institute, Zibo, Shandong 255314, P.R. China, Department of Immunology, Cancer Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100021, P.R. China, Department of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212000, P.R. China
Published online on: November 13, 2015 https://doi.org/10.3892/ol.2015.3918
Pages: 809-816

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

The cancer‑testis (CT) family of antigens are expressed in multiple types of malignant neoplasm and are silent in normal tissues, apart from the testis. Immunotherapy targeting CT antigens is a promising therapeutic strategy for treatment of solid tumors. One member of this family, melanoma‑associated antigen A4 (MAGE‑A4), has been demonstrated to be expressed in melanomas and lung cancer. Patients with tumors expressing the MAGE‑A4 antigen exhibit specific cellular and humoral immune responses to the antigen, resulting in a favorable prognosis. Conversely, the expression of MAGE‑A4 is associated with poor survival in lung cancer. Myeloid‑derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells, which are upregulated in the cancer microenvironment. Little is known regarding any potential correlation between the expression of MAGE‑A4 antigens and the accumulation of MDSCs. The present study aimed to examine the association between circulating MDSC levels and MAGE‑A4 expression in a mouse model of Lewis lung cancer. The expression of MAGE‑A4 in tumor cells or tissues was evaluated using western blotting, while the percentage of MDSCs (CD11b+Gr‑1+) in the blood was detected by flow cytometry. In addition, the suppressive capacity of MDSCs and the effectiveness of MDSC depletion were assessed in C57BL/6 tumor‑bearing mice. MDSCs were demonstrated to upregulate MAGE‑A4 expression via the phosphosphorylated‑signal transducer and activator of transcription 3705 pathway, while depletion of MDSCs decreased the tumor growth rate, prolonged median survival and enhanced the recognition of MAGE‑A4 by CD8+ T cells. These findings indicated that immunotherapeutic strategies involving induction of cytotoxic T lymphocytes that target MAGE‑A4, in combination with MDSC depletion, may be an effective approach to immunotherapy for cancer types with high expression of MAGE‑A4.

View Figures

View References

1	Zhi X: The Sixth South-North forum of lung cancer in China was held in CPPCC auditorium. Zhongguo Fei Ai Za Zhi. 16:661–662. 2013.(In Chinese). PubMed/NCBI
2	Shigematsu Y, Hanagiri T, Shiota H, Kuroda K, Baba T, Mizukami M, So T, Ichiki Y, Yasuda M, So T, et al: Clinical significance of cancer/testis antigens expression in patients with non-small cell lung cancer. Lung Cancer. 68:105–110. 2010. View Article : Google Scholar : PubMed/NCBI
3	Coulie PG, Karanikas V, Lurquin C, Colau D, Connerotte T, Hanagiri T, Van Pel A, Lucas S, Godelaine D, Lonchay C, et al: Cytolytic T-cell responses of cancer patients vaccinated with a MAGE antigen. Immunol Rev. 188:33–42. 2002. View Article : Google Scholar : PubMed/NCBI
4	Baba T, Shiota H, Kuroda K, Shigematsu Y, Ichiki Y, Uramoto H, Hanagiri T and Tanaka F: Clinical significance of human leukocyte antigen loss and melanoma-associated antigen 4 expression in smokers of non-small cell lung cancer patients. Int J Clin Oncol. 18:997–1004. 2013. View Article : Google Scholar : PubMed/NCBI
5	Dhodapkar MV, Osman K, Teruya-Feldstein J, Filippa D, Hedvat CV, Iversen K, Kolb D, Geller MD, Hassoun H, Kewalramani T, et al: Expression of cancer/testis (CT) antigens MAGE-A1, MAGE-A3, MAGE-A4, CT-7 and NY-ESO-1 in malignant gammopathies is heterogeneous and correlates with site, stage and risk status of disease. Cancer Immun. 3:92003.PubMed/NCBI
6	Bolli M, Kocher T, Adamina M, Guller U, Dalquen P, Haas P, Mirlacher M, Gambazzi F, Harder F, Heberer M, et al: Tissue microarray evaluation of melanoma antigen E (MAGE) tumor-associated antigen expression: Potential indications for specific immunotherapy and prognostic relevance in squamous cell lung carcinoma. Ann Surg. 236:785–793. 2002. View Article : Google Scholar : PubMed/NCBI
7	Yakirevich E, Sabo E, Lavie O, Mazareb S, Spagnoli GC and Resnick MB: Expression of the MAGE-A4 and NY-ESO-1 cancer-testis antigens in serous ovarian neoplasms. Clin Cancer Res. 9:6453–6460. 2003.PubMed/NCBI
8	Yoshida N, Abe H, Ohkuri T, Wakita D, Sato M, Noguchi D, Miyamoto M, Morikawa T, Kondo S, Ikeda H, et al: Expression of the MAGE-A4 and NY-ESO-1 cancer-testis antigens and T cell infiltration in non-small cell lung carcinoma and their prognostic significance. Int J Oncol. 28:1089–1098. 2006.PubMed/NCBI
9	Zou W and Chen L: Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 8:467–477. 2008. View Article : Google Scholar : PubMed/NCBI
10	Ostrand-Rosenberg S and Sinha P: Myeloid-derived suppressor cells: Linking inflammation and cancer. J Immunol. 182:4499–4506. 2009. View Article : Google Scholar : PubMed/NCBI
11	Gabrilovich DI and Nagaraj S: Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 9:162–174. 2009. View Article : Google Scholar : PubMed/NCBI
12	Gabrilovich DI, Ostrand-Rosenberg S and Bronte V: Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 12:253–268. 2012. View Article : Google Scholar : PubMed/NCBI
13	Marcar L, Maclaine NJ, Hupp TR and Meek DW: Mage-A cancer/testis antigens inhibit p53 function by blocking its interaction with chromatin. Cancer Res. 70:10362–10370. 2010. View Article : Google Scholar : PubMed/NCBI
14	Srivastava MK, Zhu L, Harris-White M, Huang M, St John M, Lee JM, Salgia R, Cameron RB, Strieter R, Dubinett S, et al: Targeting myeloid-derived suppressor cells augments antitumor activity against lung cancer. Immunotargets Ther. 2012:7–12. 2012.PubMed/NCBI
15	Srivastava MK, Zhu L, Harris-White M, Kar UK, Huang M, Johnson MF, Lee JM, Elashoff D, Strieter R, Dubinett S, Sharma S, et al: Myeloid suppressor cell depletion augments antitumor activity in lung cancer. PLoS One. 7:e406772012. View Article : Google Scholar : PubMed/NCBI
16	Groeper C, Gambazzi F, Zajac P, Bubendorf L, Adamina M, Rosenthal R, Zerkowski HR, Heberer M and Spagnoli GC: Cancer/testis antigen expression and specific cytotoxic T lymphocyte responses in non small cell lung cancer. Int J Cancer. 120:337–343. 2007. View Article : Google Scholar : PubMed/NCBI
17	Cui NP, Xie SJ, Han JS, Ma ZF, Chen BP and Cai JH: Effective adoptive transfer of haploidentical tumor-specific T cells in B16-melanoma bearing mice. Chin Med J (Engl). 125:794–800. 2012.PubMed/NCBI
18	Morales JK, Kmieciak M, Knutson KL, Bear HD and Manjili MH: 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. 123:39–49. 2010. View Article : Google Scholar : PubMed/NCBI
19	Baumgartner CK, Ferrante A, Nagaoka M, Gorski J and Malherbe LP: Peptide-MHC class II complex stability governs CD4 T cell clonal selection. J Immunol. 84:573–581. 2010. View Article : Google Scholar
20	Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack O, Nichol G, et al: Guidelines for the evaluation of immune therapy activity in solid tumors: Immune-related response criteria. Clin Cancer Res. 15:7412–7420. 2009. View Article : Google Scholar : PubMed/NCBI
21	Daudi S, Eng KH, Mhawech-Fauceglia P, Morrison C, Miliotto A, Beck A, Matsuzaki J, Tsuji T, Groman A and Gnjatic S: Expression and immune responses to MAGE antigens predict survival in epithelial ovarian cancer. PLoS One. 9:e1040992014. View Article : Google Scholar : PubMed/NCBI
22	Chaux P, Luiten R, Demotte N, Vantomme V, Stroobant V, Traversari C, Russo V, Schultz E, Cornelis GR, Boon T, et al: Identification of five MAGE-A1 epitopes recognized by cytolytic T lymphocytes obtained by in vitro stimulation with dendritic cells transduced with MAGE-A1. J Immunol. 163:2928–2936. 1999.PubMed/NCBI
23	Gunda V, Cogdill AP, Bernasconi MJ, Wargo JA and Parangi S: Potential role of 5-aza-2′-deoxycytidine induced MAGE-A4 expression in immunotherapy for anaplastic thyroid cancer. Surgery. 154:1456–1462. 2013. View Article : Google Scholar : PubMed/NCBI
24	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
25	Nagorsen D, Scheibenbogen C, Marincola FM, Letsch A and Keilholz U: Natural T cell immunity against cancer. Clin Cancer Res. 9:4296–4303. 2003.PubMed/NCBI
26	Cuenca AG, Cuenca AL, Winfield RD, Joiner DN, Gentile L, Delano MJ, Kelly-Scumpia KM, Scumpia PO, Matheny MK, Scarpace PJ, et al: Novel role for tumor-induced expansion of myeloid-derived cells in cancer cachexia. J Immunol. 192:6111–6119. 2014. View Article : Google Scholar : PubMed/NCBI
27	Duffour MT, Chaux P, Lurquin C, Cornelis G, Boon T and van der Bruggen P: A MAGE-A4 peptide presented by HLA-A2 is recognized by cytolytic T lymphocytes. Eur J Immunol. 29:3329–3337. 1999. View Article : Google Scholar : PubMed/NCBI
28	Kobayashi T, Lonchay C, Colau D, Demotte N, Boon T and van der Bruggen P: New MAGE-4 antigenic peptide recognized by cytolytic T lymphocytes on HLA-A1 tumor cells. Tissue Antigens. 62:426–432. 2003. View Article : Google Scholar : PubMed/NCBI
29	Zhang Y, Stroobant V, Russo V, Boon T and van der Bruggen P: A MAGE-A4 peptide presented by HLA-B37 is recognized on human tumors by cytolytic T lymphocytes. Tissue Antigens. 60:365–371. 2002. View Article : Google Scholar : PubMed/NCBI
30	Scanlan MJ, Altorki NK, Gure AO, Williamson B, Jungbluth A, Chen YT and Old LJ: Expression of cancer-testis antigens in lung cancer: Definition of bromodomain testis-specific gene (BRDT) as a new CT gene, CT9. Cancer Lett. 150:155–164. 2000. View Article : Google Scholar : PubMed/NCBI
31	Schumacher K, Haensch W, Röefzaad C and Schlag PM: Prognostic significance of activated CD8 (+) T cell infiltrations within esophageal carcinomas. Cancer Res. 61:3932–3936. 2001.PubMed/NCBI
32	Cruz CR, Gerdemann U, Leen AM, Shafer JA, Ku S, Tzou B, Horton TM, Sheehan A, Copeland A, Younes A, et al: Improving T-cell therapy for relapsed EBV-negative Hodgkin lymphoma by targeting upregulated MAGE-A4. Clin Cancer Res. 17:7058–7066. 2011. View Article : Google Scholar : PubMed/NCBI
33	Segura E and Villadangos JA: Antigen presentation by dendritic cells in vivo. Curr Opin Immunol. 21:105–110. 2009. View Article : Google Scholar : PubMed/NCBI
34	Willimsky G and Blankenstein T: Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature. 437:141–146. 2005. View Article : Google Scholar : PubMed/NCBI
35	Drake CG, Jaffee E and Pardoll DM: Mechanisms of immune evasion by tumors. Adv Immunol. 90:51–81. 2006. View Article : Google Scholar : PubMed/NCBI
36	Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ and Montero AJ: Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother. 58:49–59. 2009. View Article : Google Scholar : PubMed/NCBI
37	Meyer C, Cagnon L, Costa-Nunes CM, Baumgaertner P, Montandon N, Leyvraz L, Michielin O, Romano E and Speiser DE: Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol Immunother. 63:247–257. 2014. View Article : Google Scholar : PubMed/NCBI
38	Shen P, Wang A, He M, Wang Q and Zheng S: Increased circulating Lin(−/low) CD33(+) HLA-DR(−) myeloid-derived suppressor cells in hepatocellular carcinoma patients. Hepatol Res. 44:639–650. 2014. View Article : Google Scholar : PubMed/NCBI
39	Bianchi G, Borgonovo G, Pistoia V and Raffaghello L: Immunosuppressive cells and tumour microenvironment: Focus on mesenchymal stem cells and myeloid derived suppressor cells. Histol Histopathol. 26:941–951. 2011.PubMed/NCBI
40	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
41	Sevko A and Umansky V: Myeloid-derived suppressor cells interact with tumors in terms of myelopoiesis, tumorigenesis and immunosuppression: Thick as thieves. J Cancer. 4:3–11. 2013. View Article : Google Scholar : PubMed/NCBI
42	Umansky V and Sevko A: Tumor microenvironment and myeloid-derived suppressor cells. Cancer Microenviron. 6:169–177. 2013. View Article : Google Scholar : PubMed/NCBI
43	Jungbluth AA, Ely S, DiLiberto M, Niesvizky R, Williamson B, Frosina D, Chen YT, Bhardwaj N, Chen-Kiang S, Old LJ, et al: The cancer-testis antigens CT7 (MAGE-C1) and MAGE-A3/6 are commonly expressed in multiple myeloma and correlate with plasma-cell proliferation. Blood. 106:167–174. 2005. View Article : Google Scholar : PubMed/NCBI
44	Forghanifard MM, Gholamin M, Farshchian M, Moaven O, Memar B, Forghani MN, Dadkhah E, Naseh H, Moghbeli M, Raeisossadati R, et al: Cancer-testis gene expression profiling in esophageal squamous cell carcinoma: Identification of specific tumor marker and potential targets for immunotherapy. Cancer Biol Ther. 12:191–197. 2011. View Article : Google Scholar : PubMed/NCBI
45	Nagao T, Higashitsuji H, Nonoguchi K, Sakurai T, Dawson S, Mayer RJ, Itoh K and Fujita J: MAGE-A4 interacts with the liver oncoprotein gankyrin and suppresses its tumorigenic activity. J Biol Chem. 278:10668–10674. 2003. View Article : Google Scholar : PubMed/NCBI
46	Park JH, Kong GH and Lee SW: hMAGE-A1 overexpression reduces TNF-alpha cytotoxicity in ME-180 cells. Mol Cells. 14:122–129. 2002.PubMed/NCBI
47	Iclozan C, Antonia S, Chiappori A, Chen DT and Gabrilovich D: Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer. Cancer Immunol Immunother. 62:909–918. 2013. View Article : Google Scholar : PubMed/NCBI
48	Waight JD, Netherby C, Hensen ML, Miller A, Hu Q, Liu S, Bogner PN, Farren MR, Lee KP, Liu K, et al: Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis. J Clin Invest. 123:4464–4478. 2013. View Article : Google Scholar : PubMed/NCBI