Science The reason why tumors inactivate nearby immune cells

When cancer occurs in the human body, tumor cells begin to grow, divide and eventually spread
.
But what makes these new tumor cells able to evade the body's immune system? The body's immune system is used to recognize and ward off attacks from these defective
cells.
The answer to this long-standing question for scientists could be the key to unlocking more effective cancer treatments — therapies that can disable the subversive activity of tumors and allow the immune system to function
.

Now, a team led by researchers at Harvard Medical School has discovered a way that tumor cells can shut down the immune system, allowing tumors to grow
unchecked.
The study was conducted mainly in mice and was published in the journal Science on Sept.
29
.
Studies have shown that tumor cells with specific mutations release a chemical, a metabolite, that weakens nearby immune cells, reducing their ability to
kill cancer cells.

The findings reveal key details of how tumors inactivate the immune system and highlight the role
of tumor metabolites in this process.
The findings also point to the important role
that the region around the tumor — the tumor microenvironment — plays in cancer growth.
If further research is conducted, these results may eventually help scientists develop better, more targeted treatments for cancers
fueled by this mechanism.

Marcia Haigis, professor of cell biology at HMS Blavatnik Institute and senior author, said: "Our study highlights the immune component in this cancer, which was not fully understood
before.
We now know that metabolites produced by tumor cells can affect nearby immune cells, reducing
the hostility of the surrounding environment to cancer.
”

Causes cancer

For the past 15 years, Haigis' lab has been studying the mechanisms that trigger cancer, including tumor metabolites
that help cancer cells survive and grow.
The study led Haigis and his colleagues to the immune system, which inhibits tumor growth
by sending immune cells to the tumor microenvironment to kill tumor cells.
But how exactly do tumors and immune cells interact? Why do some tumors escape immune attacks while others cannot?

Haigis said: "We are very interested in
understanding how metabolites mediate the interaction between tumor cells and immune cells.
"

The scientists decided to focus their work on
tumors with mutations in the isocitrate dehydrogenase (IDH) gene.
IDH mutations occur in about 3.
5 percent of cancers, including solid cancers such as gliomas and blood cancers such as acute myeloid leukemia
.
In fact, about 80% of low-grade gliomas and secondary gliomas have IDH mutations
.
Tumor cells carrying this mutation secrete D-2-hydroxyglutaric acid (D-2HG), a metabolite that is not normally abundant in the human body
.

Previous studies have shown that D-2HG helps tumor cells grow
by altering their genetic pathway, permanently transforming them into a more aggressive, rapidly dividing state.
However, few studies have investigated how D-2HG affects other cells in the tumor microenvironment, including CD8+ T cells, which release proteins called granzymes and other immunochemicals called cytokines to kill cancer cells
.

Haigis explains: "Our understanding of this image is incomplete because most of the attention is focused on understanding how this metabolite directly affects cancer cells, while its effects on surrounding cells are rarely explored
.
"

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

First, the researchers determined that CD8+ T cells sense D-2HG in their surroundings and absorb
it.
Next, they demonstrated that once CD8+ T cells are exposed to the concentration of D-2HG produced by the tumor, the immune cells immediately slow down their proliferation and lose the ability to
kill the tumor cells.
Specifically, D-2HG inactivates T cells by inhibiting a key metabolic enzyme called lactate dehydrogenase, which plays a role in producing cytokines and granulases to help T cells proliferate and maintain the tumor killing capacity
of T cells.
When D-2HG was removed, the T cells regained the ability to kill tumor cells, suggesting that the process was reversible
.

In another set of experiments, the scientists monitored D-2HG and CD8+ T cells
in IDH-mutant human glioma tumors.
They found that tumor regions with higher D-2HG levels had lower levels of T cell infiltration, while tumor regions with higher levels of T cells had lower levels of D-2HG — thus supporting the discovery
of a mouse model.

Haigis said: "We found that this metabolite secreted by the tumor hijacked the body's normal defense mechanisms and caused it to collapse
.
" However, she stresses, "This is only part of the puzzle, and the main problems in the field remain.
"
For example, she hopes that future studies will look deeper into D-2HG to identify more targets and explore how metabolites affect other cells in the tumor microenvironment — including other immune cells
.
"

Haigis said: "The initial focus of the field was on the function of this metabolite in tumor cells, and I think it has now opened the door for other studies to see how it affects immune cells and the microenvironment as a whole
.
" She added that such work could extend beyond D-2HG to study how other metabolites secreted by tumors reshape the tumor microenvironment
.
Haigis' lab also recently published a paper in Cell Metabolism showing that the lactic acid produced by tumor cells similarly reduces the anti-cancer abilities
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.
IDH inhibitors are existing drugs that inhibit tumor growth by blocking IDH mutations to reduce the production of D-2HG
.
"We still don't know the therapeutic implications of this study — does IDH inhibitors work by increasing the active part of the immune system, or does it only act directly on cancer cells?" Haigis asked
.
Haigis emphasized that her research focuses on revealing the basic biology
of how tumor cells use metabolites to suppress the immune system.
However, she hopes that in the long run, scientists may be able to use her findings, as well as other research, to develop therapies
that harness the interactions between cancer cells and immune cells.

Giulia Notarangelo, Jessica B.
Spinelli, Elizabeth M.
Perez, Gregory J.
Baker, Kiran Kurmi, Ilaria Elia, Sylwia A.
Stopka, Gerard Baquer, Jia-Ren Lin, Alexandra J.
Golby, Shakchhi Joshi, Heide F.
Baron, Jefte M.
Drijvers, Peter Georgiev, Alison E.
Ringel, Elma Zaganjor, Samuel K.
McBrayer, Peter K.
Sorger, Arlene H.
Sharpe, Kai W.
Wucherpfennig, Sandro Santagata, Nathalie Y.
R.
Agar, Mario L.
Suvà , Marcia C.
Haigis.
Oncometabolite d-2HG alters T cell metabolism to impair CD8+T cell function.
Science, 2022; 377 (6614): 1519