Suppression of the hyaluronic acid pathway induces M1 macrophages polarization via STAT1 in glioblastoma

Abstract

Immunosuppressive tumor microenvironment is a crucial factor that impedes the success of tumor immunotherapy, and tumor-associated macrophages (TAMs) are essential for the formation of tumor immunosuppressive microenvironment. Hyaluronic acid (HA) is highly important brick for glioblastoma microenvironment, but whether it contributes to TAM polarization and glioblastoma immunosuppressive microenvironment is less well known. In our study, we observed that disrupting glioblastoma HA synthesis or blocking HA binding to its receptor CD44 on macrophages increased the proportion of M1 macrophages by upregulating SIRPα in macrophages, the underlying mechanism was elevated SIRPα enhanced STAT1 phosphorylation and suppressed STAT3 phosphorylation in macrophages. Subsequently, the induced macrophages could inhibit glioblastoma growth via a feedback effect. In addition, 4-methylumbelliferone (4MU), a cholecystitis drug, can disrupt the CD47/SIRPα axis by disturbing glioblastoma HA synthesis. Collectively, these findings indicated that HA plays a crucial role in macrophages polarization and CD47/SIRPα signaling between glioblastoma cells and macrophages, and suppressing the HA pathway may be a new immunotherapeutic approach for glioblastoma.

CD44 expressed by myeloid cells promotes glioma invasion

“…Altogether, failure to upregulate MMP9 and reduction in pro-inflammatory cytokines indicate an altered pro-tumorigenic polarization of CD44 -/- myeloid cells in response to GBM. In agreement with this, a recent study has found that HA synthetized by glioma cells binds CD44 on myeloid cells thereby triggering their immunosuppressive polarization ( 55 ). Authors showed that by blocking CD44 on macrophages, the latter acquire an M1 phenotype resulting in reduced glioma proliferation and migration and increased survival of tumor-bearing mice.…”

TAM-targeted reeducation for enhanced cancer immunotherapy: Mechanism and recent progress

“…Notably, the interaction of CD44 with HA is also regulated by a variety of cytokines such as IL-2, tumor necrosis factor (TNF), and chemokines, which activates CD44 to enhance the HA-CD47 interaction ( 41 ). A recent study shows that disruption of tumor HA synthesis or blocking HA binding to CD44 on TAM effectively increased the proportion of M1-TAMs by upregulating SIRPα ( 42 ). Besides, HA also binds to other receptors such as TLR4, which inhibit the lipopolysaccharide-induced activation of inflammatory macrophages or monocytes ( 43 ).…”

Targeting copper death genotyping associated gene RARRES2 suppresses glioblastoma progression and macrophages infiltration

“…The M0 phenotype is considered an attenuated M2 phenotype, which is associated with tumor immunosuppression [ 24 ]. M1 macrophages and activated NK cells can inhibit tumor progression [ 25 , 26 ]. In summary, these observations indicated that GBM patients with high risk scores were more likely to have an immunosuppressive microenvironment.…”

“…Moreover, patient risk scores were negatively correlated with M1 macrophage and activated NK cell infiltration and positively correlated with M0 macrophage infiltration. M1 macrophages can produce proinflammatory factors, which are thought to be associated with tumor suppression [ 25 ]. The M0 phenotype is considered the attenuated M2 phenotype, while the M2 phenotype is considered associated with tumor angiogenesis and the formation of a tumor immunosuppressive microenvironment [ 24 ].…”