PDPN contributes to constructing immunosuppressive microenvironment in IDH wildtype glioma

Abstract

The tumor immunosuppressive microenvironment (IME) significantly affects tumor occurrence, progression, and prognosis, but the underlying molecular mechanisms remain to make known. We investigated the prognostic significance of PDPN and its role in IME in glioma. Weighted gene co-expression network analysis (WGCNA) found PDPN closely related to IDH wildtype status and higher immune score. Correlation analysis suggested PDPN was highly positively relevant to immune checkpoints expression and immune checkpoints block responding status. Correlation analysis together with verification in vitro suggested PDPN highly positively relevant tumor-associated neutrophils (TANs) and tumor-associated macrophages (TAMs). Least absolute shrinkage and selection operator (LASSO) regression employed to develop the prediction model with TANs and TAMs markers showed that high risk scores predicted worse prognosis. We highlight that PDPN overexpression is an independent prognostic indicator, and promotes macrophage M2 polarization and neutrophil degranulation, ultimately devotes to the formation of an immunosuppressive tumor microenvironment. Our findings contribute to re-recognizing the role of PDPN in IDH wildtype gliomas and implicate promising target therapy combined with immunotherapy for this highly malignant tumor.

M2 macrophage marker CHI3L2 could serve as a potential prognostic and immunological biomarker in glioma by integrated single‐cell and bulk RNA‐Seq analysis

“…29,30 Wang et al revealed the immunosuppressive microenvironment roles of Podoplanin (PDPN) in glioma with IDH wildtype. 31 Zhang et al successfully established a tryptophan metabolism-based model in glioma to predict these patients' prognosis and immune responses. 32 Liu et al showed that DNTTIP2 was significantly linked with macrophage infiltrations in…”

“…Tumor microenvironment and immune cell infiltration have gradually been regarded as hotspots in glioma and they could be used to predict patents’ prognosis or immune responses 29,30 . Wang et al revealed the immunosuppressive microenvironment roles of Podoplanin (PDPN) in glioma with IDH wildtype 31 . Zhang et al successfully established a tryptophan metabolism‐based model in glioma to predict these patients’ prognosis and immune responses 32 .…”

Exploring Monocytes-Macrophages in Immune Microenvironment of Glioblastoma for the Design of Novel Therapeutic Strategies

“…IDH status also denote TME cell components differences between tumors with the wild-type isoform and those with the mutated IDH [ 48 ]. Unlike GBMs with IDH-wildtype, GBMs with the IDH mutation have been shown to have less M2 macrophage infiltration and fewer PD-1-expressing T cells [ 49 ]. A study based on samples from patients with GBM showed that there is less infiltration of TAMs in GBM with IDH mutation, being more proinflammatory, which could reflect a better prognosis for these patients, and the fact that microglia in mutated IDH also have a proinflammatory role [ 50 ].…”

Exosome‐transmitted podoplanin promotes tumor‐associated macrophage‐mediated immune tolerance in glioblastoma

“…PDPN‐positive cancer‐associated fibroblasts have been implicated with immune suppression in pancreatic adenocarcinoma and lung cancer 18,19 . In gliomas, PDPN expression is elevated in accordance with tumor malignancy 20 and correlated with radioresistance 21,22 . However, how PDPN regulates macrophage polarization in glioma remains unclear.…”