Targeting Myeloid-Derived Suppressor Cell-Mediated Immunotherapy Resistance in Pediatric Brain Cancer 2260592

Abstract

Abstract Introduction Despite the decrease in childhood cancer mortality, a cure for certain tumors remains elusive. The survival rates for high-grade medulloblastoma are disappointing, pointing to the immediate need for creative therapeutic strategies. In the tumor microenvironment (TME), suppressor cells inhibit the immune system, which includes myeloid-derived suppressor cells- a heterogeneous population of immature myeloid cells that play a role in cancer progression and metastasis. Two subsets of these cells, granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs), promote this immunosuppressive milieu by inhibiting anti-tumor T cell activity. Methods Monocytes were co-cultured with HTB-186 cells in a transwell system to generate tumor-educated MDSCs. CFSE-labeled T cells were co-cultured with MDSCs and stimulated with anti-CD3/CD28 beads. Proliferation was analyzed by flow cytometry (FACSCanto, FlowJo v10). Data were analyzed using GraphPad Prism 8.0 (t-test, mean ± SEM). Results Our study revealed that M-MDSCs serve as a biomarker for high-grade, metastatic pediatric cancers, including medulloblastoma. Our findings suggest that high concentrations of the soluble factors GM-CSF and IL-6, which are produced by HTB-186 medulloblastoma cells, lead to the induction of medulloblastoma M-MDSCs. M-MDSCs from medulloblastomas are highly immunosuppressive and exert their suppressive function by inducing reactive oxygen species (ROS). Our data indicate that GM-CSF from medulloblastoma cells induces ROS production in M-MDSCs via the coordinated activation of p47phox, a critical subunit of the NOX2 NAPDH oxidase, by STAT3 and NF-κB, resulting in inhibition of T cells leading to immune suppression in the TME. Conclusion In conclusion, our study identifies M-MDSCs as key drivers of immune suppression in high-grade pediatric medulloblastoma. These findings highlight M-MDSCs as promising therapeutic targets to overcome immune suppression and improve outcomes in pediatric brain tumors. Funding Source PON2 728 2300001864 and PON2728 2400001585 to KY Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)