Searching for subtypes of immune cells seen only in the most serious, grade 4 brain tumors, called glioblastomas, and using a recently developed technology called spatial genomics, the researchers found that glioblastoma stem cells were co-localized with a type of immunosuppressive cell called myeloid-derived suppressor cell (MDSC), and that these two cells symbiotically feed off of each other to promote tumor growth and aggressiveness. A description of the work was published Jan. 17 in the journal Science. “Tumor stem cells represent only 5% to 10% of the tumor, but they’re the critical cells that are renewing and generating the rest of the tumor and are essentially responsible for the aggressiveness of the tumor,” says senior study author Drew Pardoll, M.D., Ph.D., the Martin D. Abeloff Professor of Cancer Research , co-director of the Mark Foundation Center for Advanced Genomics and Imaging, and director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy. “We found that the myeloid-derived suppressor cells and tumor stem cells literally were in the same place — a region described by pathologists in the 1980s as the pseudopalisading region. There was a very intimate connection.”

To better characterize the cellular components of brain cancer, investigators performed single-cell RNA sequencing on tissue samples from 33 types of brain tumors spanning from low to high grade, finding two populations of MDSCs in IDH-WT glioblastoma. Then, using a technique called spatial transcriptomics to look at patterns of gene expression of over 750,000 immune cells and more than 350,000 tumor and associated cells in these samples, they found MDSCs were co-located with the tumor stem cells.

“Glioblastoma is a highly aggressive brain tumor with remarkable ability to evade the immune system, which has made immune-based therapies largely ineffective to this point,” said first and co-corresponding author, Christina Jackson, M.D., an assistant professor of neurosurgery at the Perelman School of Medicine at the University of Pennsylvania, who was at Johns Hopkins at the time the research was conducted. “Our study revealed a distinct subset of immune cells, known as myeloid-derived suppressor cells that promote glioblastoma growth, providing new insights into how the tumor interacts with the immune system. By identifying these cells and their role, we hope to uncover new therapeutic targets andlay the groundwork for more effective treatments.”

In their studies, investigators discovered that the two types of cells were feeding each other in the brain tumors. Tumor stem cells were producing chemical signals called chemokines that attracted the MDSCs, and making growth factors and activation factors for the MDSCs. In turn, the MDSCs were producing growth factors for the tumor cells.

The researchers were able to further ascertain what specific molecules tumor stem cells were producing to attract and activate MDSCs. Two of the key ones identified by the team were IL (interleukin)-6 and IL-8, which play a role in inflammatory responses, and for which MDSCs have receptors.

“IL-8 is one of the major attractants to bring the MDSCs to the tumor, and IL-6 is one of the major activators of the MDSCs,” Pardoll says.

On the flip side, the team found that MDSCs secreted a growth factor called fibroblast growth factor 11 (FGF11) to feed the stem cells, a molecule never before known to be involved in brain or other cancers.

Along the way, Jackson, Pardoll and colleagues found that tumors with a mutation in the IDH1 gene, which are less aggressive, had almost no MDSCs and far fewer cancer stem cells. This led them to look across all brain cancers at the correlation between MDSC infiltration and survival. Using the National Cancer Institute’s Cancer Genome Atlas (TCGA) database of cancer samples, they indeed found that very tight correlation — the fewer cancer stem cells and fewer MDSCs a person had in their tumors, the better they did.

While additional studies are needed to further understand these cellular interactions, the work is exciting in that it suggests additional potential targets to block in treatment of these aggressive brain tumors, Pardoll says. For example, Jamie Spangler, Ph.D., an associate professor of biomedical engineering at Johns Hopkins, has developed an investigational bispecific antibody that binds to the receptors for IL-6 and IL-8, blocking their signaling.

Study co-authors were 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 of Johns Hopkins. Other researchers contributing to the work were from Stanford University School of Medicine in California.

The research was supported by 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 is a consultant for Bionaut Labs, Privo Technologies, Haystack Oncology and Depuy-Synthes. He also is a co-founder of OrisDx and Belay Diagnostics. Yegnasubramanian has received grant support through Johns Hopkins from Bristol Myers Squibb and Janssen and grants and personal fees from Cepheid. He is a co-founder of Digital Harmonic and Brahm Astra Therapeutics. Elisseeff is founder of Aegeria Soft Tissue. Powell is an employee of Calico but was not when this research was performed. Pardoll is a consultant for Amgen, Arcturus Therapeutics, ATengen, Bristol Myers Squibb, Compugen, Dragonfly Therapeutics, Immunomic Therapeutics, Normunity, PathAI, RAPT Therapeutics, Regeneron, Takeda Pharmaceuticals and Tizona. He has received grant support through Bristol Myers Squibb, Compugen, Enara Bio and Immunomic Therapeutics, and owns stock in Dracen Pharmaceuticals, Dragonfly Therapeutics, Enara Bio, RAPT Therapeutics and Tizona. Pardoll is on the board of directors of Clasp Therapeutics and Dracen Pharmaceuticals and has patent royalties with Bristol Myers Squibb and Immunomic Therapeutics. These relationships are managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.

In reality, research has shown that human bodily responses and cognitive shifts affect each other in both directions. We feel sorry because we cry, but also cry when feeling sorry. So how then for our primate cousins? To date, their connections have remained largely unexplored.

Now a team of researchers at Kyoto University has led a study on six Japanese macaques living in KyotoU’s Center for the Evolutionary Origins of Human Behavior, in Aichi prefecture. The researchers focused on self-scratching — a bodily response linked to negative emotions like anxiety and fear — and its relationship to pessimistic judgment bias, which is the tendency to expect a negative outcome when faced with ambiguous information.

By presenting the monkeys with a white rewarding button and a black non-rewarding button, together with a gray ambiguous button, the researchers were able to estimate each monkey’s degree of pessimism. They also videoed the monkeys to identify the timing of self-scratching, analyzing the relationship between self-scratching and pessimism.

“Bodily responses associated with negative emotions can predict subsequent cognitive pessimism,” says corresponding author Sakumi Iki, “but not the other way around.”

In other words, the monkeys were more likely to make pessimistic judgments — avoiding the gray button — immediately after self-scratching, yet making a pessimistic judgment did not necessarily lead to self-scratching. This stands in contrast to humans, for whom evidence suggests a pessimistic way of thinking can cause bodily responses. That this influence did not appear in the macaques suggests that their emotional bodily responses may precede cognitive changes.

From an evolutionary standpoint, the coping strategy of first addressing immediate needs through bodily responses and then engaging in cognitive information processing is probably adaptive for dealing with challenges in natural habitats. Thus, this mechanism might have existed long before humans and macaques diverged, pointing to an evolutionarily conserved system.

“In humans, the relationship between mind and body may have evolved in a distinctive way, influenced by our use of language and advanced introspection,” adds Iki.

“But it might be observable in monkeys if different bodily reactions or cognitive processes are examined.”

Future research involving a wider range of primates and other animals could shed more light on the evolutionary origins of human emotions, and deepen our understanding of the connection between the mind and the body.