Studies in mice by researchers at Harvard Medical School have identified a way that cancer cells can turn off the immune system, allowing the tumor to grow unchecked. The results showed that tumor cells with a particular mutation release a metabolite that weakens nearby immune cells, rendering them less capable of killing the cancer cells. The results also pointed to the essential role that the tumor microenvironment (TME) plays in cancer growth. If supported through further research, the results could point to the development of more targeted therapies to better treat cancers that are fuelled by the newly identified mechanism.

“Our study highlights an immune component in this type of cancer that wasn’t fully appreciated before,” said research lead Marcia Haigis, PhD, professor of cell biology in the Blavatnik Institute at HMS. “We now know that a metabolite produced by tumor cells can impact nearby immune cells to make the surrounding environment less hostile for the cancer.” Haigis is senior author of the team’s published paper in Science, which is titled “Oncometabolite D-2HG alters T cell metabolism to impair CD8+ T cell function.”

Cancers start with the rapid growth and spread of tumor cells. But what enables these tumor cells to dodge the body’s immune system, which is designed to identify and destroy defective cells? “The discovery of mutations in genes encoding key metabolic enzymes has highlighted a direct link between altered metabolism and disease,” the authors noted. One example is gain-of-function mutations in the gene encoding the enzyme isocitrate dehydrogenase (IDH) in human cancers. These mutations result in production of D-2-hydroxyglutarate (D-2HG), an oncometabolite that can promote tumorigenesis, but which isn’t normally found at high levels in the human body.

The Haigis lab has been studying the mechanisms that fuel cancer, including such tumor metabolites that help cancer cells survive and grow. Their newly reported work looked specifically at the interaction between tumor metabolites and 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? “We became really interested in understanding how metabolites mediate the cross talk between tumor cells and immune cells,” Haigis said.

The team focused on tumors with IDH mutations. IDH mutations occur in around 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 and secrete D-2-hydroxyglutarate (D-2HG).

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 in the tumor microenvironment (TME), including CD8+ T cells — immune cells that release proteins called granzymes and other immune chemicals called cytokines to kill cancer cells. “Despite our understanding of the cancer cell–intrinsic regulation of epigenetics by D-2HG, the tumor cell–nonautonomous effects of D-2HG in the TME still remain poorly understood,” the investigators wrote. “ … the mechanisms by which D-2HG alters antitumor immunity remain unknown.”

Haigis further explained, “We had an incomplete picture because much of the focus has been on understanding how this metabolite directly affects cancer cells, whereas its impact on the surrounding cells has been less explored.”

For the newly reported study, graduate student and first author Giulia Notarangelo led a series of experiments in mouse models to elucidate how D-2HG interacts with CD8+ T cells in the tumor microenvironment.

First, the researchers established that CD8+ T cells sense D-2HG in their environment and take it up. Next, they demonstrated that as soon as CD8+ T cells were exposed to a concentration of D-2HG produced by a tumor, the immune cells immediately slowed down their proliferation and lost their ability to kill tumor cells. “ … tumor-derived D-2HG was taken up by CD8+ T cells and altered their metabolism and antitumor functions in an acute and reversible fashion,” they wrote.

Specifically, D-2HG deactivated T cells by inhibiting a key metabolic enzyme called lactate dehydrogenase (LDH) that plays a role in producing cytokines and granzymes, helping T cells proliferate, and maintaining T cells’ tumor-killing capacity. When D-2HG 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 D-2HG and CD8+ T cells in human glioma tumors with IDH mutations.  They found that tumor regions with higher D-2HG levels had lower levels of T-cell infiltration, while tumor regions with more T cells had lower D-2HG levels — thus supporting the mouse model findings. “Our results suggest that D-2HG may not only affect tumor initiation and growth through tumor cell-intrinsic mechanisms but also by directly affecting the cells in the surrounding TME,” the team noted. “We propose that D-2HG acts directly on CD8+ T cells in the TME of IDH-mutant tumors by altering their metabolic and cytotoxic signatures … Our findings show that D-2HG alters glucose metabolism in CD8+ T cells, resulting in impaired proliferation, cytokine production, and cytotoxicity.”

T cell Take Down: Researchers discover how cancer cells manipulate the immune system from Harvard Medical School on Vimeo.

“What we found is that this metabolite secreted by the tumor hijacks the body’s normal defense mechanism and causes it to break down,” Haigis said. She emphasized, however, that “this is only one part of the puzzle, and major questions in the field remain.”

For example, she hopes future research will delve deeper into D-2HG to identify additional targets and explore how the metabolite affects other cells — including other immune cells — in the tumor microenvironment.

“The field has initially focused on tumor 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 said. Such work, she added, could extend beyond D-2HG to investigate how other metabolites secreted by tumors remodel the tumor microenvironment.

Haigis’ lab recently published a paper in Cell Metabolism showing that lactate produced by tumor cells similarly reduces the cancer-killing ability of nearby CD8+ T cells. Haigis is also interested in understanding the importance of this D-2HG–T cell mechanism in patients treated with IDH inhibitors — existing drugs that combat tumor growth by blocking IDH mutations to reduce D-2HG production. “ … we found that many of the effects caused by D-2HG are reversible upon D-2HG removal,” the authors noted. “In the future, it will be interesting to determine whether therapeutic interventions involving US Food & Drug Administration–approved, mutation-specific IDH inhibitors potentiate immune responses by removing immunosuppressive D-2HG from the TME, in addition to having a direct role in the inhibition of tumor growth.”

Haigis acknowledged, “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?”

She emphasized that her research focuses on unraveling the basic biology of how tumor cells use metabolites to suppress the immune system. However, Haigis is hopeful that in the long term, scientists may be able to use her findings, along with additional research, to develop therapies that take advantage of the interaction between cancer cells and immune cells.

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