Cyclooxygenase-mediated IL-10Rα signaling underlies pro-tumor phenotypes of macrophages in glioma.

Tumor-associated macrophages (TAMs) in glioblastoma (GBM) often adopt tumor-supportive phenotypes, but the underlying signaling in TAMs is unclear. Interleukin-10 (IL-10) is frequently upregulated in tumors, but the understanding of IL-10 in the tumor immune microenvironment is controversial. This study aims to determine the roles of IL-10 receptor alpha (IL-10Rα) signaling in TAMs and explore the targetable mediators for GBM treatment. We found that growth of intracranial GBMs was delayed in engineered mice with myeloid-specific knock-out of IL-10Rα, which was accompanied by changes in TAM phenotypes. Meanwhile, IL-10 expression in GBMs, which was largely accredited to TAMs, were not affected by IL-10Rα deficiency. RNA-sequencing analysis and immunostaining revealed cyclooxygenases COX-1/2 as potential downstream effectors of IL-10Rα in TAMs. Pharmacological inhibition of COX-1/2 suppressed bone-marrow derived macrophages (BMDM) polarization upon IL-4/IL-10 treatment. Consistently, the COX inhibitor NS-398 mitigated intracranial GBM growth. In summary, we not only demonstrated the crucial roles of IL-10Rα but also discovered COX-1/2 as downstream targets for pro-tumor phenotypes of TAMs in GBMs. These findings provide new clues for future development of immunotherapies for GBM treatment.