A type of aggressive brain tumor resistant to treatment has a different population of immune cells that support their growth, according to new research directed by researchers in the Johns Hopkins Kimmel Bloommel Bloommel Institute Institute for Cancer Immunotherapy Cancer Center and the Faculty of the University of Johns Hopkins of medication.
Looking subtypes of immune cells observed only in the most severe grade brain tumors, called glioblastomas, and using a recently developed technology called space genomic, the researchers found that glioblastoma stem cells were located with a type of immunosuppressive cells called myloid myloids . -The derivative suppressor cell (MDSC), and that these two cells feed symbiotically with each other to promote tumor growth and aggressiveness. A description of the work was published on January 17 in the magazine Science. “Tumor stem cells represent only 5% to 10% of the tumor, but they are the critical cells that are renewing and generating the rest of the tumor and are essentially responsible for the aggressiveness of the tumor,” says the senior study author attracted A Pardoll, MD, Ph.D., Cancer Research Professor at Martin D. Abeloff, co -director of the Mark Foundation Center for Genomics and Advanced Images, and director of the Bloomberg ~ Kimmel Institute for cancer immunotherapy. “We found that the suppressor cells derived from myeloids and tumor stem cells were literally in the same place, a region described by pathologists in the 1980s as the Pseudopalina region. There was a very intimate connection.”
To better characterize the cellular components of brain cancer, the researchers made sequencing of individual cells RNA in tissue samples of 33 types of brain tumors that cover low to high degree, finding two populations of MDSC in the IDH-WT glioblastoma. Then, using a technique called spatial transcriptomic to observe gene expression patterns of more than 750,000 immune cells and more than 350,000 tumors and associated cells in these samples, they found that the MDSCs were located together with tumor stem cells.
“Glioblastoma is a highly aggressive brain tumor with a remarkable ability to evade the immune system, which has made immune therapies ineffective to this point,” said First and Co-Corregon Author, Christina Jackson, MD, assistant teacher of neurosurgery At Perelman Medicine School of the University of Pennsylvania, which was in Johns Hopkins at the time the investigation was conducted. “Our study revealed a different subset of immune cells, known as suppressive cells derived from myeloids that promote glioblastoma growth, providing new ideas on how the tumor interacts with the immune system. By identifying these cells and their role, we hope to discover new new Therapeutics.
In their studies, researchers discovered that the two types of cells fed each other in brain tumors. Tumor stem cells produced chemical signals called chemiocins that attracted MDSC and manufactured growth factors and activation factors for MDSC. In turn, MDSC were producing growth factors for tumor cells.
Researchers could determine even more what specific molecules were producing tumor stem cells to attract and activate MDSC. Two of the key identified by the team were IL (interleucin) -6 and IL -8, which play a role in inflammatory responses, and for which MDSCs have receptors.
“IL-8 is one of the main attractants that leads to the MDSC to the tumor, and IL-6 is one of the main activators of the MDSC,” says Pardoll.
On the other hand, the team discovered that the MDSC secreted a growth factor called Fibroblast Growth Factor 11 (FGF11) to feed stem cells, a molecule that was never known before being involved in the brain or other types of cancer.
Along the way, Jackson, Pardoll and his colleagues found that tumors with a mutation in the IDH1 gene, which are less aggressive, almost did not have MDSC and much less cancer stem cells. This led them to look through all brain cancers the correlation between infiltration and survival of MDSC. Using the Database of the Cancer Cancer Genome Genome of the National Cancer Institute (TCGA) of cancer samples, they discovered that the very narrow correlation: the less cancer stem cells and the less MDSC that a person had in their tumors, the better they did better .
While additional studies are needed to better understand these cellular interactions, work is exciting because it suggests additional potential objectives to block these aggressive brain tumors, says Pardoll. For example, Jamie Spangler, Ph.D., associate professor of biomedical engineering at Johns Hopkins, has developed a biespecific research antibody that binds to the receptors for IL-6 and IL-8, blocking their signaling.
The co -authors of the study were Christopher Cherry, Sadhana Bom, Arbor Dykema, Rulin Wang, Elizabeth Thompson, Ming Zhang, Runczhe Li, Zhicheng Ji, Wenpin Hou, Wentao Zhan, Hao Zhang, John Choi, Ajay Vaghasia, Landon Hansen, Kate Jones, Kate Jones, Kate Jones, Kate Jones, Kate Jones, Kate Jones, Kate Fausto Rodríguez, Jon Weingart, Calixto-Hope Lucas, Jonathan Powell, Jennifer Elisseeff, Srinivasan Yegnasubramanian, Chetan Bettegowda and Hongkai Ji by Johns Hopkins. Other researchers who contributed to work were from the Stanford University Faculty in California.
The Research was Supported by the National Institute of Health (GRANTS #F32NS108580, #R01HG010889, R01HG009518, RA37C K Foundation for Cancer Research, A Burroughs Wellcom Race Prize for Medical Scientists, the Commonwealth Foundation, the Maryland cigarette restitution and the NiH Pioneer Prize.
Bettegowda is a Bionaut Labs consultant, Proco Technologies, Haystack Oncology and Debuy-Synthes. He is also co -founder of Orisdx and Bellay’s diagnostics. Yegnasubramanian has received support from subsidies through Johns Hopkins by Bristol Myers Squibb and Janssen and subsidies and personal fees from Cepheid. He is co -founder of Digital Harmonic and Brahm Astra Therapeutics. Elisseeff is the founder of Aegegeria Soft Tisse. Powell is a Calico employee, but it was not when this research was conducted. Pardoll is an Amgen consultant, Arcturus Therapeutics, Atangen, Bristol Myers Squibb, Compugen, Dragonfly Therapeutics, Immunomic Therapeutics, Normunery, Pathai, Rapt Therapeutics, Regeneron, Takeda Pharmaceuticals and Tizona. He has received support from subsidies through Bristol Myers Squibb, Compuge, Enara Bio and Immunomic Therapeutics, and has stocks in Dracen Pharmaceuticals, Dragonfly Therapeutics, Enara Bio, Rapt Therapeutics and Tizona. Pardoll is located at the Board of Directors of Therapeutics and Dracen Pharmaceuticals and has patent royalties with Bristol Myers Squibb and Immunomic Therapeutics. These relationships are administered by Johns Hopkins University according to their interest conflict policies.