When cancer develops in the body, it begins with tumor cells that rapidly multiply and divide before spreading. But how are these nascent tumor cells able to evade the body’s immune system, which is designed to recognize and defend against such faulty cells? The answer to this long-unsolved topic may hold the key to more successful cancer treatments — medications that block tumors’ subversive moves and allow the immune system to do its job.

Researchers at Harvard Medical School have now discovered a mechanism through which tumor cells can disable the immune system, enabling the tumor to spread unchecked. The study, which was conducted primarily in mice and published today in Science, demonstrates that tumor cells with a certain mutation generate a chemical, known as a metabolite, that weakens adjacent immune cells, making them less capable of eliminating cancer cells.

The results underscore the crucial roles played by tumor metabolites in the deactivation of the immune system by malignancies. The findings also highlight the crucial part that the tumor microenvironment—the region around the tumor—plays in the development of cancer.

If more research elucidates the data, it could help scientists design better, more focused treatments for tumors whose growth is supported by this mechanism.

Professor of cell biology at the Blavatnik Institute at Harvard Medical School and senior author Marcia Haigis said that this study “highlights an immune component in this type of cancer that wasn’t fully appreciated before.

“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.”

Supporting Cancer

The Haigis lab has spent the last 15 years researching the mechanisms that support cancer, including tumor metabolites that support cancer cell growth and survival. Haigis and colleagues’ study led them to the immune system, which inhibits the growth of tumors by sending immune cells into the tumor microenvironment to annihilate tumor cells. But how precisely do immune cells and tumors interact? Why do certain cancers withstand the immune onslaught but not others?

“We became really interested in understanding how metabolites mediate the cross-talk between tumor cells and immune cells,” Haigis added.

The experts decided to focus their work on tumors with a change in a gene called isocitrate dehydrogenase, or IDH. Around 3.5 percent of tumors, including solid cancers like gliomas and blood cancers like acute myeloid leukemia, have IDH mutations. In reality, IDH mutations are present in about 80% of low-grade gliomas and secondary glioblastomas. This mutation causes tumor cells to emit D-2-hydroxyglutarate (D-2HG), a metabolite that is not typically present in large concentrations in the human body.

Previous research has demonstrated that D-2HG promotes tumor cell growth by permanently changing the genetic pathways of these cells to make them more aggressive and capable of dividing more quickly. While CD8+ T cells are immune cells that generate granzymes and other immune molecules called cytokines to attack cancer cells, very little research has examined how D-2HG impacts these cells and other cells in the tumor microenvironment.

“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,” Haigis said.

Giulia Notarangelo, a graduate student who is the study’s first author, oversaw a series of tests in animal models to determine how D-2HG affects CD8+ T cells in the tumor microenvironment.

The researchers first demonstrated that CD8+ T lymphocytes recognize and uptake D-2HG when it is present in their surroundings. They then showed that CD8+ T cells instantly slowed down their proliferation and lost their capacity to eradicate tumor cells when they were exposed to a concentration of D-2HG produced by a tumor. D-2HG specifically deactivated T cells by inhibiting lactate dehydrogenase, a vital metabolic enzyme that aids in the production of cytokines and granzymes, promotes T cell proliferation, and preserves T cells’ capacity to attack tumors. The T cells were able to once again kill tumor cells when D-2HG was taken out, indicating that the procedure is reversible.

In a different series of tests, the researchers observed CD8+ T cells and D-2HG in human glioma tumors with IDH mutations. They discovered that while tumor locations with fewer T cells had higher levels of T-cell infiltration, tumor regions with more T cells had lower levels of D-2HG, corroborating the results from the mouse model.

“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 added. She stressed, however, that “this is only one part of the puzzle, and major questions in the field remain.”

She anticipates that more in-depth studies of D-2HG will uncover new targets and examine how the metabolite influences other cells, such as immune cells, in the tumor microenvironment.

The field initially concentrated on this metabolite’s effects on tumor cells, but Haigis believes that the door is now open for more studies to examine how it affects immune cells and the entire microenvironment. She also said that this kind of work could go beyond D-2HG and look into how other metabolites made by tumors change the environment inside the tumor.

Recent research from Haigis’ team in Cell Metabolism demonstrates that lactate produced by tumor cells also lowers the capacity of neighboring CD8+ T lymphocytes to combat cancer.

Haigis is especially curious about the significance of this D-2HG-T cell pathway in patients receiving IDH inhibitor therapy, which slows the growth of tumors by preventing IDH mutations that increase D-2HG synthesis.

“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?”

Haigis stressed that the main goal of her research is to figure out how tumor cells use metabolites to stop the immune system from working. She is optimistic, though, that in the long run, researchers will be able to apply her discoveries and other research to create treatments that make use of the interaction between cancer cells and immune cells.

Source: 10.1126/science.abj5104

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