Blood monocyte-derived CD169+ macrophages contribute to antitumor immunity against glioblastoma

Abstract

Infiltrating tumor-associated macrophages (TAM) are known to impede immunotherapy against glioblastoma (GBM), however, TAMs are heterogeneous, and there are no clear markers to distinguish immunosuppressive and potentially immune-activating populations. Here we identify a subset of CD169+ macrophages promoting an anti-tumoral microenvironment in GBM. Using single-cell transcriptome analysis, we find that CD169+ macrophages in human and mouse gliomas produce pro-inflammatory chemokines, leading to the accumulation of T cells and NK cells. CD169 expression on macrophages facilitates phagocytosis of apoptotic glioma cells and hence tumor-specific T cell responses. Depletion of CD169+ macrophages leads to functionally impaired antitumor lymphocytes and poorer survival of glioma-bearing mice. We show that NK-cell-derived IFN-γ is critical for the accumulation of blood monocyte-derived CD169+ macrophages in gliomas. Our work thus identifies a well-distinguished TAM subset promoting antitumor immunity against GBM, and identifies key factors that might shift the balance from immunosuppressive to anti-tumor TAM.

Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma

“…In 2015, we were the first to show that in most patients with GBM, the sub-ventricular zone (SVZ) of the lateral ventricles is a reservoir of cancer stem-like cells (CSCs) that show distinct patterns of treatment resistance compared to matched CSCs from the tumor mass, and contribute to seeding of the recurrent tumor 4,5 . Despite the extensive inter-tumor heterogeneity within GBM, in nearly 80% of patients, the SVZ classifies as the molecular subtype with the worst prognosis 4 , characterized by the presence of tumor-associated macrophages (TAMs) 6–28 , which consist of monocyte-derived macrophages (MDM) and microglia. Therefore, identifying therapeutic targets in the SVZ is key to developing more effective treatments.…”

The Role of Hypoxia in Brain Tumor Immune Responses

“…Therefore, researchers are investigating strategies to block inhibitory immune mediators. In addition to T cells, phagocytes including macrophages, microglia, and neutrophils can participate in the antitumor response via phagocytosis [ 54 55 56 ]. Unconventional T cells such as NK cells, natural killer T (NKT) cells, mucosal-associated invariant T cells (MAIT cells), and γδ T cells are also involved in antitumor responses ( Fig.…”

Immunity in malignant brain tumors: Tumor entities, role of immunotherapy, and specific contribution of myeloid cells to the brain tumor microenvironment

“…On the other hand, CD169+ MoMac-TAMs were depicted to promote antitumor inflammation in GBM and reflect a beneficial subset of MoMacs [89]. These MoMacs support T-cell accumulation by enhancing phagocytosis of glioma cells and secretion of proinflammatory chemokines [89]. MHC class II antigen presentation on MoMacs was necessary for functional T-cell toxicity and its loss leads to CD8 T-cell dysfunction via osteopontin [90].…”

“…S100A4 is a small calcium-binding protein and revealed to avoid apoptosis in TAMs in different tumor models [88]. On the other hand, CD169+ MoMac-TAMs were depicted to promote antitumor inflammation in GBM and reflect a beneficial subset of MoMacs [89]. These MoMacs support T-cell accumulation by enhancing phagocytosis of glioma cells and secretion of proinflammatory chemokines [89].…”