Better View of Immune Landscape Leads to New Targets for Cancer Therapy

By Julie Grisham,

Wednesday, November 11, 2015

Stained melanoma tissue

In a recent study, MSK investigators considered the mechanism of an enzyme regulator called IDO and found that blocking it may be an effective therapy for certain cancers because of the effect it has on other parts of the immune system.

  • Many human cancers have high levels of IDO, an enzyme that helps regulate the immune system.
  • IDO affects regulatory T cells and myeloid-derived suppressor cells, both of which help cancer grow.
  • Researchers say IDO is a good target for cancer therapies because it’s central to other immune responses.

Cancer treatment is becoming more precise and increasingly targeted to specific genetic mutations in patients’ tumors. In addition to the growing number of drugs that target those genetic changes, the use of immunotherapy drugs that harness the body’s own immune system to fight cancer is also expanding.

This makes learning about the immune system’s role in individual patients’ tumors an imperative for precision medicine. Now a study led by Memorial Sloan Kettering scientists is providing new clues about the immune system and the role it plays in cancer.

Immunotherapy is a growing area of cancer research.

“The more we move into the world of immunotherapy, the more we realize that the immune landscape of each tumor is important to take into consideration when you’re designing a therapeutic approach,” says MSK tumor immunologist Taha Merghoub. “I think it’s important not just for immunotherapy but for designing any therapies.”

An Enzyme Called IDO

In a recent study, published in the journal Cell Reports, the investigators looked at the mechanism of an enzyme called IDO, which helps regulate the immune system. Their findings indicate that blocking IDO may be an effective therapy for certain cancers because of the effect that IDO has on other parts of the immune system.

Earlier research had shown that IDO permits tumor cells to escape detection by the immune system by affecting the tumor’s microenvironment — the area that surrounds the tumor. A range of human cancer types have been found to have high levels of IDO.

The investigators looked at the relationship between IDO and two types of cells that were known to control how the immune system recognizes and responds to tumors. These cells were regulatory T cells (Tregs), which help restrain immune responses and allow tumors to escape detection by the immune system, and myeloid-derived suppressor cells (MDSCs), which have been associated with tumors’ ability to develop resistance to therapy.

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An Important Therapeutic Target

“In immunotherapy, there are drugs to target Tregs, drugs to target myeloid suppressor cells, and drugs to target IDO,” explains Dr. Merghoub, who was the study’s co-senior author, along with MSK physician-scientist Jedd Wolchok. “What we showed here is that IDO is an especially good target because it’s central to all of the other immune responses in this setting.”

IDO is central to other immune responses.

The lead author, MSK research fellow Rikke Holmgaard, and colleagues in Dr. Wolchok’s lab generated a tool to express high levels of IDO in tumor cells and studied the effects. They also looked at what happened when the IDO protein was blocked. It was known that IDO leads to Treg activation, and here they found that preventing Tregs from activating inhibits tumors from recruiting MDSCs. “These findings really tied everything together,” Dr. Merghoub says. “If you lose IDO, you lose these other immune effects that help tumors to survive.”

They then used mouse models of breast cancer that express high levels of IDO and samples from patients’ tumor cells — primarily patients with melanoma — to confirm their findings.

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Making Medicine More Precise

Dr. Merghoub says the findings are applicable to any cancers that have a lot of MDSCs, which would include subgroups of many types of cancer. “To develop a clinical approach to treating patients, you could do immune profiling to find out if tumors have a lot of myeloid cells,” he says. “You could then develop a basket study that would stratify and group patients based on the immune landscape of their tumors, rather than where in the body the cancer was located.”

Researchers could develop basket studies based on tumors’ immune profiles.

He notes that future studies will also look at combining drugs that block IDO with other types of immunotherapies.

“Everyone agrees that genomic studies are a key part of precision medicine,” Dr. Merghoub concludes. “But I believe at some point these personalized treatments will also be based on the immune landscape of the tumors in addition to genomic identification.”

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This research was supported by Swim Across America, the Ludwig Institute for Cancer Research, and the Breast Cancer Research Foundation.

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