Myeloid derived suppressor cell infiltration of murine and human gliomas is associated with reduction of tumor infiltrating lymphocytes

Abstract

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.