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Editing traitorous genes to fight cancer

Scientists deleted genes responsible for "traitorous cells" that stop the immune system from fighting brain cancer.

Image Credit: Photo by National Cancer Institute on Unsplash

A glioblastoma is an incredibly common and aggressive brain tumor. Patients who are diagnosed with this cancer live a mere 15 months on average, and less than 5% of them live for more than five years. Unfortunately, typical cancer treatments like chemotherapy and surgery are largely ineffective on glioblastoma, since they have a hard time targeting only the cancerous brain cells. 

Since other treatments aren’t very effective, scientists are attempting to reprogram immune cells to directly fight tumors, using a treatment called immunotherapy. Scientists hypothesize glioblastoma should be an excellent target for immunotherapy, since immune cells can cross into the brain more readily than other bloodborne cancer treatments. 

Despite their best efforts, researchers have thus far failed to use immunotherapy treatments to successfully fight glioblastoma, largely because the tumor itself has developed a special strategy to repel immune cells that might harm it. The glioblastoma carries out this strategy by attracting a defective version of one type of immune cells, called myeloid cells, that secrete signaling molecules, called cytokines

Cytokines are usually helpful in fighting off cellular invaders, because they attract other immune cells and prevent viruses from replicating. However, the cytokines produced by the defective myeloid cells actually “signal” for the body to suppress and destroy immune cells that fight tumors. 

This signaling process happens much like the chain of command in an army: the myeloid cells are like generals that issue orders and deploy troops. Unfortunately, the myeloid cells in the tumor are traitorous! They issue “orders,” represented by the cytokines, that stop “troops,” or other immune cells, from coming to the battle. This defensive strategy is regrettably quite successful and has previously rendered immunotherapy treatments useless for fighting glioblastoma. 

An international team of scientists recently found a way to make the myeloid cells work for the good guys, by changing the genes that code for them, which also changes their function. They first set out to identify the genes in the myeloid cells responsible for secreting the bad cytokines, by looking at the RNA content of over 200,000 cells from 18 different people living with a glioblastoma. The RNA analysis helps scientists identify which specific genes are turned on in a cell. 

The team first grouped the different myeloid cells into clusters with the same RNA content, or gene expression. The scientists created subclusters within these clusters based on how much of the specific genes were expressed. From looking at gene expression in these subclusters, the scientists identified which myeloid cells expressed genes that encouraged tumor growth by sending cytokines to destroy immune cells. 

Then, the scientists examined myeloid cell gene expression and patient survival data from a cancer database. They found the same traitorous genes were present in patients who survived for less than 5 years more often than in patients who survived for more than 5 years. The team interpreted the correlation between myeloid cells and patient mortality to indicate the type of myeloid cells present in the tumor influenced survival. 

In particular, these scientists identified a gene called S100A4 that was most often found in myeloid cells issuing the immune-suppressing orders. S100A4 was also present in higher levels in the tumors of patients who did not survive their glioblastoma. The scientists found this gene actually cripples the ability of other immune cells to kill cancer cells, making it impossible for these cells to bring more good guys to the fight. 

The researchers then decided to test whether or not the presence of the gene S100A4 actually affected survival rates in mice. To do this, they deleted S100A4 from the myeloid cells of one group of mice, leaving this gene intact in a control group. Then they inserted an identical glioblastoma into both groups of mice and observed how many survived. 

The scientists hypothesized mice without the gene would survive more often than mice with the gene, since erasing this gene should allow the immune cells to target cancer cells like they normally would. In line with their hypothesis, the mice without S100A4 survived longer, and more of their immune cells infiltrated the tumor.  

The researchers concluded the gene S100A4 can impede proper immune cell activity in glioblastoma. This reduction in immune cell function promotes tumor growth and decreases survivability. Deleting the gene S100A4 is a step towards improving immunotherapy techniques that allow the army of the immune system to more efficiently target and destroy cancerous cells. The researchers suggested their data will provide an effective basis for further tumor research and for combining immunotherapy methods with other current treatments. 

Study Information

Original study: Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target

Study was published on: February 9, 2022

Study author(s): Nourhan Abdelfattah, Parveen Kumar, Caiyi Wang, Jia-Shiun Leu, William F. Flynn, Ruli Gao, David S. Baskin, Kumar Pichumani, Omkar B. Ijare, Stephanie L. Wood, Suzanne Z. Powell, David L. Haviland, Brittany C. Parker Kerrigan, Frederick F. Lang, Sujit S. Prabhu, Kristin M. Huntoon, Wen Jiang, Betty Y. S. Kim, Joshy George, Kyuson Yun

The study was done at: Houston Methodist Research Institute (USA), The Jackson Laboratory for Genomic Medicine (USA), Xiangya Hospital, Central South University, (China), Weill Cornell Medical College (USA), The University of Texas MD Anderson Cancer Center (USA)

The study was funded by: NIH, Cancer Prevention & Research Institute of Texas, Department of Defense, the Houston Methodist Foundation, the Donaldson Charitable Foundation, The Peak Foundation, and the DOD Horizon Award, the University of Texas MD Anderson Moon Shots Program, the National Cancer Institute, The Broach Foundation for Brain Cancer Research, and The Elias Family Fund

Raw data availability: Data available upon request

Featured image credit: Photo by National Cancer Institute on Unsplash

This summary was edited by: Gina Misra and Aubrey Zerkle