NEW YORK – New research suggests populations of immunosuppressive myeloid-derived cells interact with certain tumor cells in an aggressive form of glioblastoma (GBM) marked by wild-type isocitrate dehydrogenase (IDH), providing metabolic and other factors that support speedy tumor growth.
"Tumor-associated myeloid cells consist of an array of phenotypes that play key roles in suppressing T-cell responses within the tumor and also modulate tumor growth," senior and co-corresponding author Drew Pardoll, a researcher affiliated with Johns Hopkins University, the Bloomberg-Kimmel Institute for Cancer Immunotherapy, and the Sidney Kimmel Comprehensive Cancer Center, and his colleagues wrote in Science on Thursday.
Still, they explained, "little is known about the specific functions of these different myeloid populations in brain tumors."
To that end, the team turned to immune cell sorting, single-cell RNA sequencing, 10x Visium spatial transcriptomics, flow cytometry-based metabolic enzyme protein analyses, and computational methods to assess more than three dozen glioma or control samples. The sample set included 21 IDH-wild type GBM samples; six grade 2 IDH-mutant oligodendrogliomas containing chromosome 1 and chromosome 19 deletions; and six grade 2, grade 3, or grade 4 IDH-mutant astrocytomas, along with five non-neoplastic brain tissue samples.
Based on data for almost 240,200 profiled immune cells, the investigators flagged 14 immune cell clusters turning up within or across a wide range of adult diffuse gliomas.
In samples of grade 4 IDH-WT GBM, in particular, the team highlighted two suspicious sets of myeloid-derived suppressor cells (MDSCs): a group of metabolically active early MDSCs (E-MDSCs) that tended to turn up in the same invasive tumor regions as stem-like GBM cells and a set of related monocytic MDSCs (M-MDSCs).
"[O]ur findings revealed a dynamic continuum of cellular states among MDSCs with immature E-MDSCs capable of transitioning into M-MDSCs," the authors wrote, "which suggests a multifaceted role in tumor progression and immune evasion."
When the team focused on high-grade IDH-mutant astrocytomas, on the other hand, it saw reduced activity by chemokines involved in attracting E-MDSCs to the tumor, along with the muted representation of E-MDSCs found in this tumor type — results that were informed by transcriptional and methylation data on low-grade gliomas and high-grade gliomas assessed by the Cancer Genome Atlas project.
Together, these and other findings supported the notion that E-MDSCs "produce growth factors that drive tumor growth and aggressiveness" in fast-growing IDH-WT GBM tumors, the authors suggested, noting that fast-growing tumor cells appeared to use certain chemokines to attract E-MDSCs, subsequently benefiting from the metabolic capabilities of the MDSCs.
Similarly, available clinical data from TCGA hinted that enhanced E-MDSC levels tended to track with poorer-than-usual survival times within IDH-WT GBM, pointing to possible prognostic clues for an E-MDSC expression signature within that cancer subtype.
Such results "suggest a potential role for E-MDSCs in promoting glioblastoma aggressiveness, likely through their interactions with tumor cells exhibiting stem-like programs," the authors wrote. "In the future, it will be critical to develop experimental models that recapitulate this critical tumor-immune interaction to mechanistically dissect it and also to test new therapeutic approaches that disrupt it."