DDW Editor Reece Armstrong explores recent research looking into why cancer cells are so effective at avoiding the body’s immune system.
Scientists may have discovered clues to why cancer cells can avoid the body’s immune system in a study conducted by researchers at Harvard Medical School.
For years now, scientists have been trying to understand why emerging tumour cells are able to dodge the body’s immune system, even though it’s designed to identify and defend against attacks from defective cells.
A team led by researchers at Harvard Medical School are hopeful it has identified that very reason, in a study which highlights a way that tumour cells turn off the immune system, allowing tumours to grow unchecked.
The research1 shows that tumours cells with a certain mutation release a metabolite, a type of chemical that weakens nearby immune cells, making them less capable of killing cancer cells. The study also highlights the role that the tumour microenvironment plays in cancer growth.
With further research, the team at Harvard Medical School hope that more targeted therapies can be developed to treat cancers whose growth is fuelled by this metabolite.
Senior author Marcia Haigis, Professor of cell biology in the Blavatnik Institute at Harvard Medical School has been working in this area for 15 years. Haigis and colleagues have been asking questions such as why certain tumours survive the immune attack, while others do not.
“We became really interested in understanding how metabolites mediate the cross talk between tumour cells and immune cells,” Haigis says.
The team decided to focus on tumours with a mutation in a gene called isocitrate dehydrogenase (IDH). IDH is thought to occur in 3.5% of cancers2, with around 80% of low-grade gliomas and secondary glioblastomas having the gene. Tumour cells that have the IDH mutated gene secrete a metabolite called D-2-hydroxyglutarate (D-2HG), something which is not normally found at high levels in the human body.
Research suggests that D-2HG enables the growth of tumours by altering their genetic pathways, transforming them into a more aggressive, rapidly dividing state. However, it’s still unknown how D-2HG affects other cells in the tumour microenvironment, including CD8+ T cells, immune cells which are linked to an ability to kill cancer cells due to them releasing proteins such as granzymes and chemicals like cytokines which can kill cancer cells.
Haigis explains that the team had an “incomplete picture” on D-2HG due to much of the research being focused on how it affects cancer cells. “Whereas its impact on the surrounding cells has been less explored,” Haigis says.
In the new study, led by graduate student and first author Giulia Notarangelo, experiments in mouse models were conducted to find out how D-2HG interacts with CD8+ T cells in the tumour microenvironment
The researchers established that CD8+ T cells sense D-2HG in their environment and take it up. The team also demonstrated that once CD8+ T cells were exposed to a concentration of D-2HG produced by a tumour, the immune cells immediately slowed down their proliferation and lost their ability to kill tumour cells.
The study showed that D-2HG deactivated T cells by inhibiting the metabolic enzyme lactate dehydrogenase, helping T cells proliferate and maintain their tumour killing capacity. However, once D-2HG was removed, the T cells could once again kill tumour cells, suggesting that the process is reversible.
Other experiments showed that tumour regions with higher D-2HG levels had lower levels of T-cell infiltration, while tumour regions with more T cells had lower D-2HG levels.
Haigis hopes that future research will explore D-2HG to identify additional targets, as well as explore how the metabolite affects other cells in the tumour microenvironment.
“The field has initially focused on tumour cell functions of this metabolite, and I think that the door is now open for other studies to look at how it impacts immune cells and the whole microenvironment,” Haigis says.
Haigis adds that this kind of work could extend beyond D-2HG to investigate how other metabolites secreted by tumours remodel the tumour microenvironment.
Haigis’ lab recently published a paper3 detailing how lactate produced by tumours can reduce the cancer-killing ability of nearby CD8+ T cells.
“We still don’t know the therapeutic implication of this research — do IDH inhibitors work in part by increasing the activity of the immune system, or do they only act directly on the cancer cells?” Haigis asks.
It’s work Haigis is looking to explore in the future.
DDW Volume 24 – Issue 1, Winter 2022/2023