Original Article

Myeloid-derived Suppressor Cells Elimination by 5-Fluorouracil Increased Dendritic Cell-based Vaccine Function and Improved Immunity in Tumor Mice


Myeloid-derived suppressor cells (MDSCs) are capable of suppressing the immune response. 5-Fluorouracil (5-FU) compared to other chemotherapy drugs have shown considerable decreases in the number of MDSCs without visible effects on T, B and natural killer cells, as well as dendritic cells (DCs). DC-based vaccines considered to be appropriate candidates for cancer immunotherapy. However, due to the presence of various factors like MDSCs in tumor microenvironment, DC vaccine cannot effectively perform its function. The purpose of this study was to evaluate the effect of low doses of 5-FU on the efficacy of DC-based vaccines in preventing and treating of melanoma tumor model. This research was performed on 28 melanoma tumor bearing C57BL/6 female mice. The mice were randomly divided to 4 groups, group 1 is control population while group 2 and 3 were treated with DC vaccine and 5-FU respectively and group 4 was treated with both DC Vaccine and 5-FU. The mice survival, tumor growth rate, number of MDSC and CD8+/ CD107a+ T cells in mice spleen were evaluated in each group with maximum result in group 4. Our results revealed that combination of DC vaccine and 5-FU reduced number of MDSCs (3%) and also tumor growth rate(10%)(p<0.05) and increased mice survival (70%) and increased CD8+ /CD107a+ T cells (25%). This study have shown that combinational therapy with DC vaccine improved immunity in tumor mice compared to the therapy consisting of DC vaccine or 5-FU only.

1. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 2012; 12(4):253-68.

2. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol. 2009;182(8):4499-506.

3. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009; 9(3):162-74.

4. Gabrilovich DI, Bronte V, Chen SH, Colombo MP, Ochoa A, Ostrand-Rosenberg S, et al. The terminology issue for myeloid-derived suppressor cells. Cancer Res 2007; 67(1):425.

5. Poschke I, Mao Y, Adamson L, Salazar-Onfray F, Masucci G, Kiessling R. Myeloid-derived suppressor cells impair the quality of dendritic cell vaccines. Cancer Immunol Immunother 2012; 61(6):827-38.

6. Bronte V, Serafini P, Apolloni E, Zanovello P. Tumor-induced immune dysfunctions caused by myeloid suppressor cells. J Immunother 2001; 24(6):431-46.

7. Suso EM, Dueland S, Rasmussen AM, Vetrhus T, et al. hTERT mRNA dendritic cell vaccination: complete response in a pancreatic cancer patient associated with response against several hTERT epitopes. Cancer Immunol Immunother 2011;60(6):809-18.

8. 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.

9. Nagasaki E, Takahara A, Koido S, Sagawa Y, Aiba K, Tajiri H, et al. Combined treatment with dendritic cells and 5-fluorouracil elicits augmented NK cell-mediated antitumor activity through the tumor necrosis factor-alpha pathway. J Immunother 2010; 33(5):467-74.

10. Inaba K, Inaba M, Romani N, Aya H, Deguchi M, Ikehara S, et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med 1992; 176(6):1693-702.

11. Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin J-P, et al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. The J Clin Invest 2010; 120(2):457-71.

12. Zisman A, Ng CP, Pantuck AJ, Bonavida B, Belldegrun AS. Actinomycin D and gemcitabine synergistically sensitize androgen-independent prostate cancer cells to Apo2L/TRAIL-mediated apoptosis. J Immunother 2001; 24(6):459-71.

13. Zhou J. Advances and prospects in cancer immunotherapy. New Journal of Science 2014;2014.

14. Stewart TJ, Smyth MJ. Improving cancer immunotherapy by targeting tumor-induced immune suppression. Cancer Metastasis Rev 2011; 30(1):125-40.

15. Whiteside TL. Disarming suppressor cells to improve immunotherapy. Cancer Immunol Immunother 2012; 61(2):283-8.

16. Menard C, Martin F, Apetoh L, Bouyer F, Ghiringhelli F. Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity. Cancer Immunol Immunother 2008; 57(11):1579-87.

17. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol 2008; 8(1):59-73.

18. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 2007; 13(9):1050-9.

19. Lacour S, Hammann A, Wotawa A, Corcos L, Solary E, Dimanche-Boitrel MT. Anticancer agents sensitize tumor cells to tumor necrosis factor-related apoptosis-inducing ligand-mediated caspase-8 activation and apoptosis. Cancer Res 2001; 61(4):1645-51.

20. Micheau O, Solary E, Hammann A, Martin F, Dimanche-Boitrel MT. Sensitization of cancer cells treated with cytotoxic drugs to fas-mediated cytotoxicity. J Natl Cancer Inst 1997; 89(11):783-9.

21. Zisman A, Ng CP, Pantuck AJ, Bonavida B, Belldegrun AS. Actinomycin D and gemcitabine synergistically sensitize androgen-independent prostate cancer cells to Apo2L/TRAIL-mediated apoptosis. J Immunother 2001; 24(6):459-71.

22. Correale P, Cusi MG, Del Vecchio MT, Aquino A, Prete SP, Tsang KY, et al. Dendritic cell-mediated cross-presentation of antigens derived from colon carcinoma cells exposed to a highly cytotoxic multidrug regimen with gemcitabine, oxaliplatin, 5-fluorouracil, and leucovorin, elicits a powerful human antigen-specific CTL response with antitumor activity in vitro. J Immunol 2005; 175(2):820-8.

23. Bauer C, Bauernfeind F, Sterzik A, Orban M, Schnurr M, Lehr HA, et al. Dendritic cell-based vaccination combined with gemcitabine increases survival in a murine pancreatic carcinoma model. Gut 2007; 56(9):1275-82.

24. Davis M, Conlon K, Bohac GC, Barcenas J, Leslie W, Watkins L, et al. Effect of pemetrexed on innate immune killer cells and adaptive immune T cells in subjects with adenocarcinoma of the pancreas. J Immunother 2012; 35(8):629-40.

25. Bang S, Kim HS, Choo YS, Park SW, Chung JB, Song SY. Differences in immune cells engaged in cell-mediated immunity after chemotherapy for far advanced pancreatic cancer. Pancreas 2006; 32(1):29-36.

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

27. Kanterman J, Sade-Feldman M, Biton M, Ish-Shalom E, Lasry A, Goldshtein A, et al. Adverse immunoregulatory effects of 5FU and CPT11 chemotherapy on myeloid-derived suppressor cells and colorectal cancer outcomes. Cancer Res 2014; 74(21):6022-35.

28. Geary SM, Lemke CD, Lubaroff DM, Salem AK. The combination of a low-dose chemotherapeutic agent, 5-Fluorouracil, and an adenoviral tumor vaccine has a synergistic benefit on survival in a tumor model system. PloS one 2013; 8(6):e67904.

IssueVol 17, No 1 (2018) QRcode
SectionOriginal Article(s)
Dendritic cell 5- Fluorouracil Myeloid-derived suppressor cell Tumor

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How to Cite
khosravianfar N, Hadjati J, Namdar A, Boghozian R, Hafezi M, Ashourpour M, Kheshtchin N, Banitalebi M, Mirzaei R, Razavi SA. Myeloid-derived Suppressor Cells Elimination by 5-Fluorouracil Increased Dendritic Cell-based Vaccine Function and Improved Immunity in Tumor Mice. Iran J Allergy Asthma Immunol. 2018;17(1):47-55.