Disarming the body’s defenders

Study shows how certain cancers neutralize T cells to subvert the immune system and help tumours grow

Human glioma tumor with a mutation showing clusters of T cells in green and pink dots represent concentrations of the metabolite D-2HG. Font: Harvard Medical School.

When cancer arises in the body, it starts with tumour cells that rapidly grow and divide and eventually spread. But what enables these nascent tumour cells to dodge the body’s immune system, which is built to identify and fend off an attack from such defective cells? The answer to this question may be the key to unlocking more effective cancer treatments. Now, a team of researchers led by the Harvard Medical School in which the researcher from the Department of Electronic, Electrical and Automatic Engineering of the Rovira i Virgili University, Gerard Baquer, has also participated, has identified a way that tumour cells can turn off the immune system, allowing the tumour to grow unchecked. The research, conducted primarily in mice and published in Science, shows that tumour cells with a particular mutation release a chemical, a metabolite, that weakens nearby immune cells, rendering them less capable of killing cancer cells.

The findings reveal critical details of how tumours deactivate the immune system and highlight the role of tumour metabolites in this process. The results also point to the essential role that the area around the tumour plays in cancer growth.

If elucidated through further research, the results could eventually help scientists develop better, more targeted therapies to treat cancers whose growth is fuelled by this mechanism.

Fuelling Cancer

How exactly do tumour and immune cells interact? Why do certain tumours survive the immune attack, while others do not? The authors of this work were especially interested in understanding how metabolites mediate the cross talk between tumour cells and immune cells. They decided to focus their work on tumours with a mutation in a gene called isocitrate dehydrogenase (IDH). IDH mutations occur in around 3.5% of cancers, including solid cancers such as gliomas and blood cancers such as acute myeloid leukaemia. In fact, approximately 80% of low-grade gliomas and secondary glioblastomas have an IDH mutation. Tumour cells that harbour this mutation secrete D-2-hydroxyglutarate (D-2HG), a metabolite not normally found at high levels in the human body.

Previous studies have shown that D-2HG aids the growth of tumour cells by altering their genetic pathways to permanently transform them into a more aggressive, rapidly dividing state. However, very little research has investigated how D-2HG affects other cells in the tumour microenvironment, including CD8+ T cells, immune cells that release proteins called granzymes and other immune chemicals called cytokines to kill cancer cells.

In their study, a first series of experiments was led in mouse models to elucidate how D-2HG interacts with CD8+ T cells in the tumour microenvironment. And in another set of experiments, the scientists monitored D-2HG and CD8+ T cells in human glioma tumours with IDH mutations. They found 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. In other words, what they found is that this metabolite secreted by the tumour hijacks the body’s normal defence mechanism and causes it to break down.

The authors of this work emphasised that their research focuses on unravelling the basic biology of how tumour cells use metabolites to suppress the immune system. They are hopeful that long-term, scientists may be able to use these findings, along with additional research, to develop therapies that take advantage of the interaction between cancer cells and immune cells.

Reference: Giulia Notarangelo, Jessica B. Spinelli, Elizabeth M. Perez, Gregory J. Baker, Kiran Kurmi, Ilaria Elia, Sylwia A. Stopka, Gerard Baquer, Jia-Ren Lin et al. Oncometabolite 2HG alters T cell metabolism to impair CD8 T cell function. Science 377(6614): 1519-1529 (2022). DOI: https://doi.org/10.1126/science.abj5104

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