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) micro-environment,
monocytic (m) MDSCs represent the predominant subset. However, the
molecular basis of mMDSC enrichment in the tumor microenvironment
compared with granulocytic (g) MDSCs has yet to be determined. Herewe
performed the first broad epigenetic profiling of MDSC subsets to define
underlying cell-intrinsic differ-ences 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 (31
and dipeptidyl peptidase-4 (DPP-4) compared with gMDSCs as part of an
enhanced cell adhesion signature. Integrin (31 blockade abrogated the
tumor- promoting phenotype of mMDSCs and altered the immune profile in
the tumor microenvironment, whereas 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 (31 and DPP-4 represent putative
immunotherapy targets to attenuate myeloid cell-driven immune
suppression in GBM.
