Deletion of the RNA regulator HuR in microglia/macrophages promotes an anti-tumor microenvironment in glioblastoma

Glioblastoma is a malignant brain tumor that portends a poor prognosis. Its resilience, in part, is related to a remarkable capacity for manipulating the microenvironment to promote its growth and survival. Microglia/macrophages are a prime target, being drawn into the tumor and stimulated to produce factors that support tumor growth and immune system evasion. Here we show that the RNA regulator, HuR, plays a key role in the tumor-promoting response of microglia/macrophages. Knockout of HuR in microglia/macrophages led to reduced tumor growth and prolonged survival in a murine model of glioblastoma. Analysis of tumor composition by flow cytometry showed that tumor associated macrophages were decreased, more polarized toward an M1-like phenotype, and had attenuated PD-L1 expression. There was a concomitant reduction in tumor-associated polymorphonuclear myeloid-derived suppressor cells, but an increase in Treg cells. In vitro assays showed reduced migration of HuR-/- microglia toward secreted factors derived from glioblastoma cells, and a decrease in migration of glioblastoma cells toward secreted factors derived from HuR-/- microglia. The molecular response of HuR-/- microglia was altered including reduced CXCL1, 2, MMP2, PD-L1 and VEGF expression and an increase in CXCL10 and several MMPs. There was a mixed effect on cytokines and other factors associated with both proinflammatory and alternatively activated phenotypes. In summary, HuR is a key modulator of the tumor microenvironment in glioblastoma, promoting tumor progression through its molecular regulation of factors produced by microglia/macrophages. These findings underscore the relevance of HuR as a therapeutic target in glioblastoma. Citation Format: Jiping Wang, Jianmei Leavenworth, Anita Hjelmeland, Ben Borg, Peter H. King. Deletion of the RNA regulator HuR in microglia/macrophages promotes an anti-tumor microenvironment in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 147.