Competing Forces: How Co-located Cell Types Propel Aggressive Brain Tumors

Investigating subtypes of immune cells specific to severe, grade 4 brain tumors known as glioblastomas, researchers employed a cutting-edge technology called spatial genomics. They discovered that glioblastoma stem cells were found alongside a type of immune cell known as myeloid-derived suppressor cells (MDSCs), indicating that these two groups support each other’s activities, enhancing tumor growth and aggression. The findings were published on January 17 in the journal Science. According to senior author Drew Pardoll, M.D., Ph.D., who holds the Martin D. Abeloff Professorship of Cancer Research, “Although tumor stem cells make up only 5% to 10% of the tumor, they are crucial for renewing and generating the rest of the tumor, thereby driving its aggressive nature.” He further noted that the MDSCs and tumor stem cells were located in the same area—a region pathologists referred to as the pseudopalisading region back in the 1980s—indicating a close relationship between the two.

To enrich the understanding of brain cancer cell types, researchers conducted single-cell RNA sequencing on tissue from 33 kinds of brain tumors, varying from low to high grade, and identified two populations of MDSCs in IDH-WT glioblastoma. They then utilized a method called spatial transcriptomics to analyze gene expression patterns in over 750,000 immune cells and more than 350,000 tumor-associated cells, revealing that MDSCs were co-located with tumor stem cells.

First author Christina Jackson, M.D., who was an assistant professor of neurosurgery at the Perelman School of Medicine at the University of Pennsylvania during the research, stated, “Glioblastoma is an extremely aggressive brain tumor that can effectively elude the immune response, rendering immune therapies largely ineffective until now. Our study has identified a distinct subset of immune cells, myeloid-derived suppressor cells, that facilitate glioblastoma proliferation, shedding light on the tumor’s interactions with the immune system. By pinpointing these cells and their functions, we aim to identify new therapeutic targets and lay the groundwork for more effective treatment options.”

The team found that the tumor stem cells and MDSCs were reciprocally influencing each other within the brain tumors. The tumor stem cells emitted chemical signals, known as chemokines, attracting MDSCs and producing growth and activation factors for these suppressor cells. In return, MDSCs provided growth factors to the tumor cells.

They were able to determine the specific molecules released by tumor stem cells that attracted and activated MDSCs. The team highlighted two important molecules identified: IL (interleukin)-6 and IL-8, which are key in inflammatory reactions and have associated receptors on MDSCs.

Pardoll explained, “IL-8 is a primary factor in luring MDSCs to the tumor, while IL-6 plays a significant role in activating these suppressor cells.”

Conversely, MDSCs were found to secrete a growth factor called fibroblast growth factor 11 (FGF11), which nourished the stem cells. This factor has not previously been associated with brain or other cancers.

Additionally, Jackson, Pardoll, and their team observed that tumors with a mutation in the IDH1 gene, which are less aggressive, had significantly fewer MDSCs and cancer stem cells. This finding prompted them to examine the relationship between MDSC infiltration and survival across all brain cancers. They analyzed data from the National Cancer Institute’s Cancer Genome Atlas (TCGA) and confirmed a strong correlation: fewer cancer stem cells and MDSCs in tumors corresponded with better patient outcomes.

Though further research is needed to delve deeper into these cellular dynamics, the findings are promising as they highlight additional potential therapeutic targets in combatting aggressive brain tumors, according to Pardoll. For example, Jamie Spangler, Ph.D., an associate professor of biomedical engineering at Johns Hopkins, has developed a bispecific antibody that targets the receptors for IL-6 and IL-8, interrupting their signaling pathways.

The study involved contributions from co-authors Christopher Cherry, Sadhana Bom, Arbor Dykema, Rulin Wang, Elizabeth Thompson, Ming Zhang, Runzhe Li, Zhicheng Ji, Wenpin Hou, Wentao Zhan, Hao Zhang, John Choi, Ajay Vaghasia, Landon Hansen, Kate Jones, Fausto Rodriguez, Jon Weingart, Calixto-Hope Lucas, Jonathan Powell, Jennifer Elisseeff, Srinivasan Yegnasubramanian, Chetan Bettegowda, and Hongkai Ji from Johns Hopkins, along with other researchers from the Stanford University School of Medicine in California.

This research received support from several sources, including the National Institutes of Health (grants #F32NS108580, #R01HG010889, R01HG009518, RA37CA230400, U07CA230691), the Neurosurgery Research Education Foundation, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the Mark Foundation for Cancer Research, a Burroughs Wellcome Career Award for Medical Scientists, the Commonwealth Foundation, the Maryland Cigarette Restitution Fund, and the NIH Pioneer Award.

Bettegowda consults for Bionaut Labs, Privo Technologies, Haystack Oncology, and Depuy-Synthes, and is a co-founder of OrisDx and Belay Diagnostics. Yegnasubramanian has received funding through Johns Hopkins from Bristol Myers Squibb and Janssen, as well as personal fees from Cepheid, and is a co-founder of Digital Harmonic and Brahm Astra Therapeutics. Elisseeff is the founder of Aegeria Soft Tissue. Powell works at Calico but was not affiliated during this research. Pardoll serves as a consultant for various biotech and pharmaceutical companies and has received grants from several organizations while holding stocks in multiple biotechnological companies. His relationships are overseen by The Johns Hopkins University to comply with conflict-of-interest policies.