An emerging strategy to target cancer may actually harm certain immune cells, according to a recent Northwestern Medicine study published in the journal Cancer Immunology, Immunotherapy.
The strategy — inhibiting an enzyme called general control nonderepressible 2 (GCN2) to boost immune system activity — is making its way through the pharmaceutical pipeline, but according to Aida Rashidi, MD, lead author of the study, scientists should be careful to avoid targeting cytotoxic T-cells with this inhibitor.
“More targeted inhibition would be a better solution for this drug, compared to global inhibition,” said Rashidi, research staff in the laboratory of Maciej (Matt) Lesniak, MD, the Michael J. Marchese Professor, chair of Neurological Surgery and senior author of the study.
Malignant glioma is an aggressive and deadly tumor in the central nervous system with nearly a 100 percent mortality rate, even with current therapies. One contributor to its lethality is immune suppression via nutrient deprivation: the cancer deprives nearby cells of glucose, oxygen and amino acids.
Amino acids are required to create new proteins, so lack of amino acids can trigger the integrated stress response (ISR). This mechanism stops global protein production — and by extension, immune system functionality — to avoid making misfolded proteins that can hurt a cell more than they help.
GCN2 functions as a trigger for the ISR, tripped when the body detects low amounts of amino acids. These findings caught the eyes of scientists searching for strategies to boost immune function against tumors.
“The idea was that if you block the GCN2 pathway, you would remove the immune suppression in the glioma microenvironment,” Rashidi said. Now, GCN2 inhibitors are being actively developed for clinical trials, but the specific effects of these inhibitors on certain immune cells are unknown.
In the current study, Rashidi and her colleagues utilized mouse models of glioma that were missing the GCN2 enzyme. In most of the body, T-cell counts were the same. However, in the tumor microenvironment, numbers of CD8+ T-cells — a “seek and destroy” white blood cell — were much lower. Furthermore, GCN2 deficiency inhibited multiple anti-tumor functions of these cells.
These results indicate that GCN2 is required for both the survival and function of CD8+ T-cell in brain tumors, according to Jason Miska, PhD, research assistant professor of Neurological Surgery and co-author of the study. Miska said he believes the low T-cell count is due to a buildup of misfolded proteins.
“If you get rid of the stress sensor and start flooding the cell with bad peptides and other compounds, the T-cells are going to die,” he said.
The scientists didn’t report on other measures of immune system function, so inhibiting GCN2 could still improve other parts of the immune system. However, they warned that a global inhibitor would likely result in these low CD8+ T-cell functionality, undercutting the utility of inhibiting the ISR in the context of immunotherapy. Instead, trimming inhibition to a small subset of cells may be the best way forward, according to Rashidi.
“You have very useless CD8s in the tumor micro environment, when you get rid of GCN2,” Rashidi said. “If this inhibition is focused on one type of cell rather than being a general blockade, that would be a better approach than just completely blocking GCN2 in all cell types.”
Miska and Lesniak are both members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Financial support comes from grants CA060553 and R35CA197725 from the National Cancer Institute (NCI), and grants R01NS093903 and 1F32NS098737-01A1 from the National Institute of Neurological Disorders and Stroke (NINDS).
