When cancer arises in the body, it starts with tumor cells that rapidly grow and divide and eventually spread. But what enables these nascent tumor 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, which long mystified scientists, may be the key to unlocking more effective cancer treatments (therapies that disable tumors’ subversive maneuvers and allow the immune system to do its job). Now, a team of researchers at Harvard Medical School has identified a way that tumor cells can turn off the immune system, allowing the tumor to grow unchecked. The research, conducted primarily in lab mice, shows that tumor cells with a particular mutation release a chemical, a metabolite, that weakens nearby immune cells, rendering them less capable of killing cancer cells. For the past 15 years, the Haigis lab has been studying the mechanisms that fuel cancer, including tumor metabolites that help cancer cells survive and grow.
The research led Haigis and colleagues to the immune system, which works to suppress tumor growth by dispatching immune cells into the tumor microenvironment to kill tumor cells. But how exactly do tumor and immune cells interact? Why do certain tumors survive the immune attack, while others do not? Well, here the so-called oncometabolites come into play. Oncometabolite refers to metabolites whose great quantity increases markedly in tumors compared with normal cells. This new term is used to describe metabolites for which 1) there is a well-characterized mechanism connecting accumulation of a certain metabolite due to mutations in metabolic enzymes; 2) there is convincing evidence for some metabolites as a predisposition to tumorigenesis. Oncometabolites are frequently associated with aberrant DNA damage, altered epigenetic responses and enable cancer cells toward metastasis. Currently, D-2-hydroxyglutarate (D2HG), L-2-hydroxyglutarate (L2HG), succinate, fumarate and lactate are recognized oncometabolites.
Mutations in metabolic enzymes subject the cells to tumorigenesis. Such changes facilitate the accumulation of metabolites that ultimately lead to epigenetic dysfunction and immunosuppression. Lab data support that both succinate and fumarate contribute to immunosuppressive polarization and T cell exhaustion, thereby making the tumor microenvironment more suitable for cell migration. In addition, fumarate could downregulate neutrophils, T-cell, and B-cell responses, inhibit dendritic cell maturation, and motivate CTLA-4 and PD-L1 expression. Finally, the accumulation of lactate also exerts an immunosuppressive effect, by inhibiting the differentiation and maturation of dendritic cells and T lymphocytes The scientists decided to focus their work on tumors with a mutation in a gene called isocitrate dehydrogenase, or IDH. These occur in around 3.5% of cancers, including gliomas, glioblastoma, kidney cancer, biliary cancers and acute myeloid leukemia.
In fact, approximately 80% of low-grade gliomas and secondary glioblastomas have an IDH mutation. Tumor cells that harbor this mutation secrete D2HG, a metabolite not normally found at high levels in the human body. Previous studies have shown that D-2HG aids the growth of tumor 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, including CD8+ T cells, that release enzymes called granzymes and cytokines to kill cancer cells. In the new study, scientists performed experiments in mice to elucidate how D-2HG interacts with CD8+ cells in the tumor microenvironment. First, the researchers established that CD8+ cells sense D2HG in their environment and take it up. Next, they demonstrated that as soon as CD8+ cells were exposed to a concentration of D-2HG produced by a tumor, they immediately slowed down their proliferation and lost their ability to kill tumor cells.
Specifically, D2HG deactivated T cells by inhibiting a key metabolic enzyme called lactate dehydrogenase that plays a role in helping T cells proliferate, and maintaining T cells’ tumor-killing capacity. When D2HG was removed, the T cells regained their ability to kill tumor cells, suggesting that the process is reversible. In another set of experiments, the scientists monitored D2HG and CD8+ cells in human glioma tumors with IDH mutations. They found that tumor regions with higher D2HG levels had lower levels of T-cell infiltration, while tumor regions with more T cells had lower D2HG levels, thus supporting the mouse-model findings. Haigis’ lab recently published a paper showing that lactate produced by tumor cells similarly reduces the cancer-killing ability of nearby CD8+ cells. Haigis is also interested in understanding the importance of this D2HG–T cell mechanism in patients treated with IDH inhibitors, new drugs that thwart tumor growth by blocking IDH mutations to reduce D2HG production.
The findings reveal critical details of how tumors deactivate the immune system and highlight the role of tumor metabolites in this process. The results also point to the essential role that the tumor microenvironmen 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 fueled by this mechanism.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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Dott. Gianfrancesco Cormaci
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