Distinct Cell Adhesion Signature Defines Glioblastoma Myeloid-Derived Suppressor Cell Subsets

Abstract

In multiple types of cancer, an increased frequency in myeloid-derived suppressor cells (MDSC) is associated with worse outcomes and poor therapeutic response. In the glioblastoma (GBM) microenvironment, monocytic (m) MDSCs represent the predominant subset. However, the molecular basis of mMDSC enrichment in the tumor microenvironment compared to granulocytic (g) MDSCs has yet to be determined. Here we performed the first broad epigenetic profiling of MDSC subsets to define underlying cell-intrinsic differences in behavior and found that enhanced gene accessibility of cell adhesion programs in mMDSCs is linked to their tumor-accelerating ability in GBM models upon adoptive transfer. Mouse and human mMDSCs expressed higher levels of integrin β1 and dipeptidyl peptidase-4 (DPP-4) compared to gMDSCs as part of an enhanced cell adhesion signature. Integrin β1 blockade abrogated the tumor-promoting phenotype of mMDSCs and altered the immune profile in the tumor microenvironment, while treatment with a DPP-4 inhibitor extended survival in preclinical GBM models. Targeting DPP-4 in mMDSCs reduced pERK signaling and their migration towards tumor cells. These findings uncover a fundamental difference in the molecular basis of MDSC subsets and suggest that integrin β1 and DPP-4 represent putative immunotherapy targets to attenuate myeloid cell-driven immune suppression in GBM.

Sequencing ofN6-methyl-deoxyadenosine at single-base resolution across the mammalian genome

“…The analysis showed 60-71% of gDNA 6mA sites can overlap very well with ATAC-seq peaks, suggesting a correlation of 6mA with accessible chromatin regions (Figure S5C). 39 We then overlapped B104-1-1 gDNA 6mA sites with the ATAC-seq peaks in data from glioblastoma tumor induced by implanted GL261 cells, 54 and observed 10-16% of gDNA 6mA sites overlapping with ATAC-seq peaks (Figure S5D). Most of these overlapped 6mA sites are within ± 1,000 and 1,500 bp ranges around ATAC-seq peak centers in NIH/3T3 cells and B104-1-1 cells, respectively, exhibiting moderate to high modification levels (Figure S5E, S5F), suggesting an association of 6mA with transcriptional activation.…”

Cellular Components of the Tumor Environment in Gliomas—What Do We Know Today?

“…The two major groups of MDSCs are derived from granulocytes (G-MDSCs) and from monocytes (M-MDSCs), but additional molecular subtypes of MDSCs have since been described [63][64][65]. Several reasons exist for the tumor-promoting properties of MDSCs in gliomas, and in addition to the expression of checkpoint proteins such as PD-L1, increased expression of arginase, integrin ß1 and dipeptidyl peptidase 4 (DPP-4) has also been described [2,63,66,68]. An important recent observation regarding MDSCs in gliomas is the demonstration of high expression of vascular non-inflammatory molecule 2 (vanin-2, VNN2) by monocyte-derived M-MDSCs in the peripheral blood of healthy individuals.…”

“…Other upregulated factors involved in promoting glioma progression include integrin ß1, which can form complexes with multiple α-subunits, and dipeptidyl peptidase 4 (DPP-4), a serine peptidase that can cleave various substrates such as chemokines. Although the exact mechanism of both compounds in relation to the activity of MDSCs is still unclear, their experimental inhibition resulted in the downregulation of ERK signaling and inhibition of MDSC migration to tumor cells [68]. Another negative regulator of the ERK pathway is dual-specificity phosphatase 3 (DUSP3), which is also involved in neovascularization in tumors [69].…”

A Cancer Prevention and Treatment Opportunity

“…Myeloid cells are critical regulators of immune and therapeutic responses to glioblastoma [62]. In the glioblastoma microenvironment, M-MDSCs represent the predominant subset [63]. M-MDSCs can be depleted by AFP-toxin conjugate [54].…”