Immunosuppressive myeloid-derived suppressor cells are increased in splenocytes from cancer patients
- 926 Downloads
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that are increased in the peripheral blood of cancer patients and limit productive immune responses against tumors. Immunosuppressive MDSCs are well characterized in murine splenic tissue and are found at higher frequencies in spleens of tumor-bearing mice. However, no studies have yet analyzed these cells in parallel human spleens. We hypothesized that MDSCs would be increased in the spleens of human cancer patients, similar to tumor-bearing mice. We compared the frequency and function of MDSC subsets in dissociated human spleen from 16 patients with benign pancreatic cysts and 26 patients with a variety of cancers. We found that total MDSCs (Linneg CD11bpos CD33pos HLA-DRneg), granulocytic MDSCs (additional markers CD14neg CD15pos), and monocytic MDSCs (CD14pos CD15neg) were identified in human spleen. The monocytic subset was the most prominent in both spleen and peripheral blood and the granulocytic subset was expanded in the spleen relative to matched peripheral blood samples. Importantly, the frequency of CD15pos MDSCs in the spleen was increased in patients with cancer compared to patients with benign pancreatic cysts and was associated with a significantly increased risk of death and decreased overall survival. Finally, MDSCs isolated from the spleen suppressed T cell responses, demonstrating for the first time the functional capacity of human splenic MDSCs. These data suggest that the human spleen is a potential source of large quantities of cells with immunosuppressive function for future characterization and in-depth studies of human MDSCs.
KeywordsMDSCs Human spleen Immunosuppression Cancer
Carboxyfluorescein succinimidyl ester
Hematoxylin and Eosin
Myeloid-derived suppressor cell
Peripheral blood mononuclear cells
This work was supported by funding provided by the University of Colorado Cancer Center Support Grant (P30CA046934), American Cancer Society 2012 Roaring Fork Valley Postdoctoral Research Award, and the Conner Family Foundation Grant.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
- 2.Mandruzzato S, Brandau S, Britten CM, Bronte V, Damuzzo V, Gouttefangeas C, Maurer D, Ottensmeier C, van der Burg SH, Welters MJ, Walter S (2016) Toward harmonized phenotyping of human myeloid-derived suppressor cells by flow cytometry: results from an interim study. Cancer Immunol Immunother 65(2):161–169CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S, Rodriguez PC, Sica A, Umansky V, Vonderheide RH, Gabrilovich DI (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7:12150CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Jordan KR, Amaria RN, Ramirez O, Callihan EB, Gao D, Borakove M, Manthey E, Borges VF, McCarter MD (2013) Myeloid-derived suppressor cells are associated with disease progression and decreased overall survival in advanced-stage melanoma patients. Cancer Immunol Immunother 62(11):1711–1722CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW (2011) Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother 60(10):1419–1430CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Goedegebuure P, Mitchem JB, Porembka MR, Tan MC, Belt BA, Wang-Gillam A, Gillanders WE, Hawkins WG, Linehan DC (2011) Myeloid-derived suppressor cells: general characteristics and relevance to clinical management of pancreatic cancer. Curr Cancer Drug Targets 11(6):734–751CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Ghansah T, Vohra N, Kinney K, Weber A, Kodumudi K, Springett G, Sarnaik AA, Pilon-Thomas S (2013) Dendritic cell immunotherapy combined with gemcitabine chemotherapy enhances survival in a murine model of pancreatic carcinoma. Cancer Immunol Immunother 62(6):1083–1091CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Porembka MR, Mitchem JB, Belt BA, Hsieh CS, Lee HM, Herndon J, Gillanders WE, Linehan DC, Goedegebuure P (2012) Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol Immunother 61(9):1373–1385CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Grizzle WE, Xu X, Zhang S, Stockard CR, Liu C, Yu S, Wang J, Mountz JD, Zhang HG (2007) Age-related increase of tumor susceptibility is associated with myeloid-derived suppressor cell mediated suppression of T cell cytotoxicity in recombinant inbred BXD12 mice. Mech Ageing Dev 128(11–12):672–680CrossRefPubMedGoogle Scholar