Myeloid derived suppressor cell infiltration of murine and human gliomas is associated with reduction of tumor infiltrating lymphocytes
- 1.1k Downloads
Myeloid derived suppressor cells (MDSCs) are bone marrow derived cells with immunosuppressive properties. We have shown previously that MDSCs numbers are elevated in the circulation of GBM patients and that they produce reversible T cell dysfunction. Here, we evaluated whether MDSCs infiltrate human GBM tissues, and whether a commonly used mouse model of GBM reproduces the biology of MDSCs that is observed in patients. We evaluated tumor specimens from patients with newly diagnosed GBM. We harvested and evaluated normal brain, tumors and hematopoietic tissues from control, vehicle and sunitinib-treated mice. In human GBM tumors, MDSCs represented 5.4 ± 1.8 % of total cells. The majority of MDSCs (CD33+HLADR−) were lineage negative (CD14−CD15−), followed by granulocytic (CD15+CD14−) and monocytic (CD15−CD14+) subtypes. In murine GBM tumors, MDSCs were 8.06 ± 0.78 % of total cells, of which more were monocytic (M-MDSC, CD11b+ Gr1-low) than granulocytic (G-MDSC, CD11b+ Gr1-high). Treatment with the tyrosine kinase inhibitor sunitinib decreased the infiltration of both granulocytic and monocytic MDSCs in murine GBM tumors. In the hematopoietic tissues, circulating G-MDSC blood levels were reduced after sunitinib treatment. In tumors, both CD3+ and CD4+ T cell counts increased following sunitinib treatment (p ≤ 0.001). Total T cell proliferation (p < 0.001) and interferon gamma production (p = 0.004) were increased in the spleens of sunitinib treated mice. Sunitinib-treated mice survived longer than vehicle-treated mice (p = 0.002). MDSCs are present in both human and mouse GBM tumors. Sunitinib may have an immunostimulatory effect, as its use is associated with a reduction in G-MDSCs and improvement in anti-tumor immune function.
KeywordsGBM MDSC Mouse model Sunitinib
This study was partly funded by a grant from Al Musella Foundation (MUSE0211BR). The authors want to acknowledge the technical assistance of Shannon Donnola for MRI Imaging. Work supported by Al Mussella Foundation, Wolf Family Foundation and NIH R01 CA150959.
Conflict of interest
The authors have no conflict of interest to disclose.
- 5.Movahedi K, Guilliams M, Van den Bossche J, Van den Bergh R, Gysemans C, Beschin A, De Baetselier P, Van Ginderachter JA (2008) Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111(8):4233–4244CrossRefPubMedGoogle Scholar
- 11.Cohen PA, Ko JS, Storkus WJ, Spencer CD, Bradley JM, Gorman JE, McCurry DB, Zorro-Manrique S, Dominguez AL, Pathangey LB, Rayman PA, Rini BI, Gendler SJ, Finke JH (2012) Myeloid-derived suppressor cells adhere to physiologic STAT3- vs STAT5-dependent hematopoietic programming, establishing diverse tumor-mediated mechanisms of immunologic escape. Immunol Invest 41(6–7):680–710CrossRefPubMedCentralPubMedGoogle Scholar
- 13.Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, Golshayan A, Rayman PA, Wood L, Garcia J, Dreicer R, Bukowski R, Finke JH (2009) Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 15(6):2148–2157CrossRefPubMedGoogle Scholar
- 19.Kohanbash G, McKaveney K, Sakaki M, Ueda R, Mintz AH, Amankulor N, Fujita M, Ohlfest JR, Okada H (2013) Granulocyte macrophage-colony stimulation factor promotes the immunosuppressive activity of glioma-infiltrating myeloid cells through interleukin-4 receptor-alpha. Cancer Res 72:6413–6423CrossRefGoogle Scholar
- 20.Dalton JE, Maroof A, Owens BM, Narang P, Johnson K, Brown N, Rosenquist L, Beattie L, Coles M, Kaye PM (2010) Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice. J Clin Invest 120(4):1204–1216CrossRefPubMedCentralPubMedGoogle Scholar
- 21.Ozao-Choy J, Ma G, Kao J, Wang GX, Meseck M, Sung M, Schwartz M, Divino CM, Pan PY, Chen SH (2009) The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res 69(6):2514–2522CrossRefPubMedCentralPubMedGoogle Scholar
- 27.Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9(1):327–337PubMedGoogle Scholar