TMIC-35. IDH1 MUTATION IN GLIOMA REPROGRAMS EARLY MYELOID DIFFERENTIATION IN THE BONE MARROW (BM) TO PRODUCE NON-IMUNESUPPRESSIVE NEUTROPHILS

Abstract

Abstract Gliomas are the most common primary brain tumors; patients exhibit a poor prognosis. Mutations in isocitrate dehydrogenase (mIDH) are present in most patients with lower grade glioma (LGG), and are correlated with better prognosis and survival. We postulated that mIDH1 induces epigenetic reprogramming leading to alteration in immune cells’ function. To examine the role of mIDH1 in the tumor immune microenvironment (TME), we generated LGG glioma models using the sleeping beauty system (Koschmann et al., 2016, Nunez et al., 2019). We show that mIDH1 gliomas exhibit increased levels of CD11b+ Gr1+ myeloid derived suppressor cells in the tumor, BM, circulation and spleen of mice. We found that mIDH1 modifies the cytokines’ repertoire in the glioma microenvironment altering the phenotype and function of the tumor infiltrating CD45+/CD11b+/Gr-1+ myeloid cells, rendering them non-immunosuppressive. Production of these cells results from activation of the granulocytic differentiation program in the BM. This novel mechanism is mediated by tumor-derived granulocyte-colony stimulating factor (G-CSF) which elicits expansion and differentiation of hematopoietic stem cells, skewing hematopoiesis towards the immature myeloid lineage. Moreover, mIDH1 glioma derived G-CSF causes mobilization of hematopoietic stem cells (HSCs) and myeloid progenitors (MPs) from BM to spleen. Blocking G-CSF in mIDH1 bearing mice significantly restored HSCs, and MPs frequencies in the spleen to levels encountered in wtIDH1 glioma. Interestingly, blocking G-CSF restored the inhibitory function of the granulocytic CD11b+ Gr-1+ in mIDH1, and shortened the median survival (MS) of mIDH1 bearing mice to the same MS encountered in wtIDH1 glioma. Our results provide insights into novel epigenetic alterations triggered by mIDH1 which regulate myeloid cells’ heterogeneity and immunosuppression; a feature that can be harnessed to develop novel immunotherapeutic strategies.