Differentiation and Immunological Function of MDSC-Derived Dendritic Cells

Abstract

Dendritic cells (DCs) play a key role in initiating and regulating immune responses, and in addition to their roles in vivo, DCs are used as natural adjuvants for various tumor vaccines. In vitro, monocytes can be used to induce DCs, but in tumor patients, due to insufficient bone marrow hematopoiesis, extramedullary hematopoiesis and tumor-associated myeloid cells expand, and monocytes mainly exist in the form of myeloid-derived suppressor cells (MDSCs). The purpose of this experiment was to explore the differences in the differentiation and immune function of DCs induced by MDSCs in tumor patients. In a mouse model, we used normal mouse bone marrow cell-derived DCs as control cells, and in a tumor-bearing model, we induced MDSCs in the spleen to generate DCs (MDSC-DCs). Through flow cytometry, we found that the production of MDSC-DCs was significantly higher than that of control mice, and the secretion of interferon-γ of MDSC-DCs was significantly reduced. Through OVA antigen presentation experiments, we found that the antigen presentation ability of MDSC-DCs was significantly decreased. Through adoptive treatment of tumor-bearing mice cells, we found that the antitumor immune function of MDSC-DCs was significantly reduced. After that, we explored the mechanism of the decrease of immune function activity of MDSC-DCs. We determined that the surface markers of MDSC-DCs were changed by flow cytometry. Through flow sorting and RNA sequencing, we found that some pathways and key gene expression in MDSC-DCs were changed. In conclusion, this study found that the immune function of MDSC-DCs decreased and explored the mechanism of the decreased immune function activity.

Keywords

MDSC-DCs / BMDCs / antitumor activity

References

[1] Banchereau J, Briere F, Caux C.et al.Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18(01): 767-811

[2] Larsen CP, Steinman RM, Witmer-Pack M, Hankins DF, Morris PJ, Austyn JM.Migration and maturation of Langerhans cells in skin transplants and explants. J Exp Med 1990; 172(05): 1483-1493

[3] Hakimeh EN, Corwin WL, Tatiana S, Alok DM, Mandoiu II, Srivastava PK.CD11c+ MHCIIlo GM-CSF-bone marrow-derived dendritic cells act as antigen donor cells and as antigen presenting cells in neoepitope-elicited tumor immunity against a mouse fibrosarcoma. Cancer Immunol Immunother 2018; 67(09): 1449-1459

[4] Sabado RL, Balan S, Bhardwaj N.Dendritic cell-based immunotherapy. Cell Res 2017; 27(01): 74-95

[5] Wu T, Dai Y.Tumor microenvironment and therapeutic response. Cancer Lett 2017; 387: 61-68

[6] Li T, Liu T, Zhu W, et al. Targeting MDSC for immune-checkpoint blockade in cancer immunotherapy: current progress and new prospects. Clin Med Insights Oncol2021; 15: 1179554921 1035540

[7] Yi H, Zhang L, Zhen Y, He X, Zhao Y.Dendritic cells induced in the presence of GM-CSF and IL-5. Cytokine 2007; 37(01): 35-43

[8] N'diaye M, Warnecke A, Flytzani S.et al. Rat bone marrow-derived dendritic cells generated with GM-CSF/IL-4 or FLT3L exhibit distinct phenotypical and functional characteristics. J Leukoc Biol 2016; 99(03): 437-446

[9] Zhao F, Obermann S, von Wasielewski R, et al. Increase in frequency of myeloid-derived suppressor cells in mice with spontaneous pancreatic carcinoma. Immunology 2009; 128(01): 141-149

[10] Kirkwood JM, Butterfield LH, Tarhini AA, Zarour H, Kalinski P, Ferrone S.Immunotherapy of cancer in 2012. CA Cancer J Clin 2012; 62(05): 309-335

[11] Zhao F, Obermann S, von Wasielewski R, , et al. Increase in frequency of myeloid-derived suppressor cells in mice with spontaneous pancreatic carcinoma. Immunology 2009; 128(01): 141-149

[12] Li B, Zhang S, Huang N.et al.CCL9/CCR1 induces myeloid-derived suppressor cell recruitment to the spleen in a murine H22 orthotopic hepatoma model. Oncol Rep 2019; 41(01): 608-618

[13] Marvel D, Gabrilovich DI.Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest 2015; 125(09): 3356-3364

[14] Inaba K, Inaba M, Romani N.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(06): 1693-1702

[15] Helft J, Böttcher J, Chakravarty P.et al.GM-CSF mouse bone marrow cultures comprise a heterogeneous population of CD11c(+)MHCII(+) macrophages and dendritic cells. Immunity 2015; 42(06): 1197-1211

[16] Thomson AW, Turnquist HR, Raimondi G.Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol 2009; 9(05): 324-337

[17] Sukhbaatar N, Hengstschläger M, Weichhart T. mTOR-mediated regulation of dendritic cell differentiation and function. Trends Immunol 2016; 37(11): 778-789

[18] Weber J, Gibney G, Kudchadkar R.et al.Phase I/II study of metastatic melanoma patients treated with nivolumab who had progressed after ipilimumab. Cancer Immunol Res 2016; 4(04): 345-353

[19] de Coaña YP, Wolodarski M, Poschke I.et al. Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma. Oncotarget 2017; 8(13): 21539-21553

[20] Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol 2014; 15(07): e257-e267

[21] Reis e Sousa C. Dendritic cells in a mature age. Nat Rev Immunol 2006; 6(06): 476-483

[22] Haidinger M, Poglitsch M, Geyeregger R.et al.A versatile role of mammalian target of rapamycin in human dendritic cell function and differentiation. J Immunol 2010; 185(07): 3919-3931

[23] Levy L, Mishalian I, Bayuch R, Zolotarov L, Michaeli J, Fridlender ZG.Splenectomy inhibits non-small cell lung cancer growth by modulating anti-tumor adaptive and innate immune response. OncoImmunology 2015; 4(04): e998469

[24] Hernandez-Quiles M, Broekema MF, Kalkhoven E.PPARgamma in metabolism, immunity, and cancer: unified and diverse mechanisms of action. Front Endocrinol (Lausanne) 2021; 12: 624112

[25] Cuaranta-Monroy I, Kiss M, Simandi Z, Nagy L.Genomewide effects of peroxisome proliferator-activated receptor gamma in macrophages and dendritic cells-revealing complexity through systems biology. Eur J Clin Invest 2015; 45(09): 964-975

[26] Veglia F, Gabrilovich DI.Dendritic cells in cancer: the role revisited. Curr Opin Immunol 2017; 45: 43-51

[27] Zhang Y, Lv D, Kim HJ.et al.A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells. Cell Res 2013; 23(03): 394-408

RIGHTS & PERMISSIONS

2022 Global Medical Genetics