How cancer disarms the body’s defenses

When cancer appears in the body, the process begins with the growth of rapidly enlarging and dividing tumor cells, eventually beginning to spread. But what allows these fledgling tumor cells to evade the immune system, which is designed to identify and defend against an attack by these faulty cells? The answer to this question may be the key to achieving more effective cancer treatments.

Now, a research team led by the Harvard University School of Medicine, in which Gerard Baquer, from the Rovira i Virgili University (URV) in Tarragona, has also participated, has identified a way in which tumor cells can deactivate the system immune system, allowing the tumor to grow uncontrollably. The research, mostly conducted in mice, shows that tumor cells with a particular mutation release a chemical, a metabolite, that weakens nearby immune cells, making them less able to fight certain cancer cells.

Their findings reveal key information about how tumors turn off the immune system and highlight the role of tumor metabolites in this process. The results of this work also point to the essential role that the area around the tumor plays in cancer growth, called the tumor microenvironment. If their results are deepened in future research, this could help the scientific community to develop more precise and powerful therapies to treat cancers whose growth is driven by this mechanism.

How exactly do tumor and immune cells interact? Why do certain tumors survive immune attack while others do not? The aim of the authors of the new study was to answer these questions and understand how metabolites mediate the dialogue between tumor cells and immune cells. Thus, they decided to focus their research on tumors with a mutation in a gene called isocitrate dehydrogenase (IDH). IDH mutations occur in approximately 3.5% of cancers, including solid cancers such as gliomas and blood cancers such as acute myeloid leukemia. In fact, approximately 80% of low-grade gliomas and secondary glioblastomas have an IDH mutation. Tumor cells harboring this mutation secrete D-2-hydroxyglutaramate (D-2HG), a metabolite not normally found at high levels in the human body.

Human glioma tumor with a mutation showing clusters of T cells in green, with pink dots representing concentrations of the D-2HG metabolite. (Image: Harvard Medical School)

Previous studies have already shown that D-2HG helps tumor cells grow by altering their genetic pathways to permanently transform them into a more aggressive and rapidly dividing state. However, few studies have yet focused on how D-2HG affects other cells in the tumor microenvironment, including CD8+ T cells, immune cells that release proteins called granzymes, and other immune chemicals called cytokines to kill cancer cells. .

In this study, a first series of experiments in mice have been carried out to elucidate how D-2HG interacts with CD8+ T cells in the tumor microenvironment. And in another set of experiments, the scientists controlled D-2HG and CD8+ T cells in human glioma tumors with IDH mutations. The results show that tumor regions with higher D-2HG levels had lower levels of T cell infiltration, whereas tumor regions with more T cells had lower D-2HG levels. In other words, their findings show that this metabolite secreted by the tumor hijacks the body’s normal defense mechanism and causes it to malfunction.

Baquer and his colleagues emphasize that their research is focused on unraveling the basic biology of how tumor cells use metabolites to suppress the immune system, and they hope that, in the long term, other scientists can use their results to develop therapies that take advantage of the interaction between cancer cells and immune cells.

The study is titled “Oncometabolite 2HG alters T cell metabolism to impair CD8 T cell function”. And it has been published in the academic journal Science. (Source: URV)