Mesenchymal stem cells and fibroblasts underly microvascular proliferation and are associated with immunosuppression and poor outcome in glioma

Immunotherapies are revolutionary cancer treatments, but resistance in solid tumors such as glioma is well-established. Cancer-associated fibroblasts are emerging as important stromal elements that contribute to treatment resistance and immunosuppression. However, cancer-associated fibroblasts and their theoretical cells of origin, mesenchymal stem cells, have not been resolved at the single-cell level directly from human glioma tissue. There is evidence that mesenchymal stem cells reside in the perivascular niche. Thus, we hypothesized glioma-associated mesenchymal stem cells and fibroblasts could be found in the perivascular niche and that they contribute to local immunosuppression and pathology such as microvascular proliferation. Microvascular proliferation is a defining histopathologic feature of high-grade glioma and independent poor prognostic marker in glioma, brain metastases, and other systemic cancers. Developing targets against microvascular proliferation could lead to biomarkers and treatments to halt progression. In this study, we demonstrate that mesenchymal stem cells and fibroblasts, herein referred to as perivascular stromal cells, underly microvascular proliferation in contrast to the classical teaching it is due to endothelial cell hyperplasia. Furthermore, we capture perivascular stromal cells in a single-cell RNA velocity analysis that suggests mesenchymal stem cells are fibroblast progenitors. With signal transduction network generation and digital spatial profiling, we show these cells participate in immunosuppressive crosstalk with myeloid cell populations in the perivascular niche. Lastly, we identify a gene signature rich in extracellular matrix molecules derived from perivascular stromal cells that have undergone microvascular proliferation with implications on overall survival in glioma and five other cancers.