Deletion of the RNA regulator HuR in tumor‐associated microglia and macrophages stimulates anti‐tumor immunity and attenuates glioma growth. Issue 12 (10th August 2019) - Wang, Jiping
Abstract: 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 prime targets, being drawn into the tumor and stimulated to produce factors that support tumor growth and evasion from the immune system. Here we show that the RNA regulator, HuR, plays a key role in the tumor‐promoting response of microglia/macrophages. Knockout (KO) of HuR led to reduced tumor growth and proliferation associated with prolonged survival in a murine model of glioblastoma. Analysis of tumor composition by flow cytometry showed that tumor‐associated macrophages (TAMs) were decreased, more polarized toward an M1‐like phenotype, and had reduced PD‐L1 expression. There was an overall increase in infiltrating CD4 + cells, including Th1 and cytotoxic effector cells, and a concomitant reduction in tumor‐associated polymorphonuclear myeloid‐derived suppressor cells. Molecular and cellular analyses of HuR KO TAMs and cultured microglia showed changes in migration, chemoattraction, and chemokine/cytokine profiles that provide potential mechanisms for the altered tumor microenvironment and reduced tumor growth in HuR KO mice. In summary, HuR is a key modulator of pro‐glioma responses by microglia/macrophages through the molecular regulation of chemokines, cytokines, and other factors. Our findings underscore the relevance of HuR as a therapeutic target in glioblastoma. Main Points: HuR deletion in tumor‐associated microglia/macrophages (TAMs) reduces malignant glioma growth and prolongs survival. HuR‐deleted TAMs are reduced in glioma tumors and develop an M1‐like phenotype and an alteration of cytokine and chemokine profiles. HuR‐deleted TAMs alter the glioma microenvironment with an increase in Infiltrating cytotoxic CD4 + and CD8 + T cells and a decrease in polymorphonuclear myeloid derived suppressor cells (PMN‐MDSC).