Cyclooxygenase-mediated IL-10Ralpha signaling underlies pro-tumor phenotypes of macrophages in glioma (PRJCA050980)
Tumor-associated macrophages (TAMs) in glioblastoma (GBM) often adopt the M2 tumor-supportive phenotype, yet little is known about the signaling in TAMs during this process. Upregulation of interleukin-10 (IL-10) is frequently observed in tumors Here, we used engineered mice with myeloid-specific knock-out of Il10ra, coding for the interleukin-10 receptor alpha (IL10RA), and studied the tumor growth and TAM differentiation in orthotopic GBMs. Disruption of Il10ra in myeloid cells resulted in retarded tumor growth, which was accompanied by the transition of TAMs into the M1 subtype. When it came to the classic downstream effectors of IL10RA, the STAT3 phosphorylation was reduced in TAMs, but IL-10 production from TAMs was not affected by Il10ra knock-out. RNA-sequencing analysis of polarized macrophages derived from wildtype and IL10ra knockout mice revealed cyclooxygenases COX-1/2 as potential effectors at the downstream of IL10RA. Inhibition of COX-1/2 with NS-398 and Loxoprofen suppressed IL-4/IL-10-induced M2 polarization of bone-marrow derived macrophages (BMDM) in vitro. Moreover, NS-398 treatment delayed intracranial GBM growth in vivo. In summary, we not only demonstrated the crucial roles of IL10RA but also discovered COX1/2 as the downstream targets for inhibition of M2 polarization of TAMs in GBMs. These findings provide new clues for future development of immunotherapies for GBM treatment.