Study Reveals How Breast Cancer Can Manipulate the Body’s Immune Signals to Grow

Breast tumors shift their microenvironment to evade an immune response

Normally, we rely on our immune system to recognize and attack foreign invaders, including cancer cells. But tumors are not passive targets; they actively reshape the immune environment around them. A new study by BCRF investigator Dr. Kornelia Polyak, published in Cancer Cell, highlights one of the ways breast cancers do this. It centers on a specific immune cell population that acts like an internal control switch. To better understand the process, Dr. Polyak and her team looked at how ductal carcinoma in situ (DCIS), also known as stage 0 breast cancer, turns into invasive breast cancer.

DCIS is very challenging to study; it is hard to get fresh tissue samples and DCIS cases with long-term follow-up to determine risk of progression. This study was a multi-institutional collaboration made possible by BCRF.

“Up to 25% of breast cancer diagnoses now in the US are DCIS,” Dr. Polyak says. “Some people progress and some don’t, and we don’t really know why and how. So, we started trying to understand the biology and figure out how we could predict who progresses.”

How breast tumors recruit immune cells as “brakes”

Previously, researchers showed that some breast cancers can evade the immune system. But a team led by Dr. Polyak demonstrated that they can not only evade the immune system but also actively build a population of immune cells that suppresses an immune response against the tumor, thereby helping it grow.

The body has an immune system made up of several types of cells. One type, T cells, can attack foreign invaders, including cancer cells. Specifically, these are called cytotoxic T cells. To prevent the immune system from becoming too aggressive and damaging the body’s own organs, the body has a failsafe: immune cells called regulatory T cells (Tregs). These T cells provide a check on the immune system—a “braking system,” in effect.

In this study, the team identified precursors to Tregs called cycling regulatory T cells (cycTregs) that are expanding in tumors and act as key “conductors” of immune suppression. Newly identified cycTregs are early, fast-dividing versions of Tregs and, in cancer, their normal protective role is perturbed: Tumors can recruit Tregs to dampen anti-tumor immune responses and help them hide and grow more easily.

Dr. Polyak’s research shows that breast cancer uses this special growing population of immune “brake” cells (cycTregs) to shut down the body’s anti-cancer response. The results reveal a new inhibitory target that may help boost the immune system by removing the brakes on the immune system that breast cancers install along the way.

“If you eliminate these cells, then you would eliminate the immunosuppressive environment,” she says.

The technologies behind the breakthroughs: single-cell sequencing and spatial transcriptomics

The team approached this project by employing two cutting-edge technologies: single-cell sequencing and spatial transcriptomics.

• Single-cell sequencing shows what each individual cell is “doing” inside a tissue. Every cell has genes, but only some of those genes are “turned on” at any moment. This technique reads which genes are active in one cell at a time.
• Spatial transcriptomics, a technique to capture RNA transcription activity in tissue, also shows which genes are active, but additionally, reveals where each cell is physically located in the tissue.

Dr. Polyak and her team leveraged these techniques to create an atlas of normal breast tissue and tumors, mapping every cell in the tumor to determine its type—immune cell, cancer cell, or support cell—and what genes are active within the cells. This let them identify rare immune populations, including cycTregs, which would have been hidden in bulk data. They also discovered that these suppressive T cells were actively expanding as DCIS progressed.

“In DCIS, we saw a lot of cytotoxic T cells,” Dr. Polyak says. “Those went down in invasive breast cancer, and at the same time, regulatory T cells went up. So that means that the invasive breast cancer has a very immunosuppressive environment, [whereas] DCIS has a very active immune environment. And then this flips when the cancer becomes invasive.”

Then when they looked at where those cells sit inside the tumor tissue, Dr. Polyak and her team found that cycTregs tend to gather in specific tumor regions, not randomly scattered but forming organized “immune suppression zones” inside the tumor.

Another discovery: cycTregs don’t work alone

By combining both technologies, the team revealed that cycTregs are actually part of a larger communication network inside the breast tumor microenvironment, the complex ecosystem around tumor cells. Their key observations include:

• Other immune and support cells in the tumor microenvironment send signals that encourage cycTreg growth.
• Interleukin-33 (IL-33), a type of protein that the immune system uses to send “alarm” and “activation” messages between cells, is a key signaling molecule for cycTreg growth.
• The OX40 gene serves as a molecular switch within the immune system, primarily controlling the extent and duration of T-cell responses. OX40 signaling supports cycTreg expansion and function, thereby enabling the tumor to evade the immune system.

Together, these factors in the microenvironment create a feedback loop that keeps immune suppression going. The result is a tumor environment where immune attack is dampened, cancer cells are less likely to be targeted, and disease progression becomes easier.

What happens as breast cancer develops

Dr. Polyak and her colleagues discovered that cycTregs appear early during the transition from DCIS to invasive disease, expand as cancer becomes more aggressive, and are linked to a weaker anti-cancer immune response. In short, as the tumor progresses, it builds up more “immune brakes.” Single-cell technology helped them drill down on this process, she says.

“We knew that invasive cancer is more immunosuppressive and that DCIS is more immunoactive, but we didn’t know the detailed mechanisms involved in what’s happening,” she says.

The team developed laboratory models to test this further and were able to show that this effect is reproducible, meaning the results can be replicated, which adds validity to the study. In addition, they tested if targeted treatments—immune checkpoint therapy (anti-PD-L1), inhibition of OX-40 or IL-33, which are part of the signaling loop that sustains immunosuppression—could release the immune brakes and stop tumor progression. In their models, they showed that dual targeting with anti-PD-L1 and OX40 or targeting the IL-33 signaling pathway markedly reduced cycTreg frequency and led to tumor regression.

“We showed with the treatment that if you can decrease their number, then you can shrink the tumor,” Dr. Polyak says.

One of the most important implications is that this system may be targetable and reversible.

Why this matters for patients

CycTregs seem to be a key reason breast tumors become “immune silent” or “immune cold.” Higher levels are associated with weaker anti-tumor immune activity, reduced diversity of immune responses, and poorer outcomes in breast cancer. This may help explain why some early cancers become invasive while others don’t.

The bottom line — and the importance of BCRF

CycTregs appear to be the central organizers of the shift from non-invasive to invasive breast cancer and may provide promising therapeutic targets to prevent immune escape and disease progression, ultimately helping immunotherapy work better.

Dr. Polyak says BCRF’s unique support model allows for innovation and experimentation, which helped make these new discoveries possible.

“BCRF funding is so important because it allows us to do things that are higher risk and take time to get resolved,” she says. “It allows us to venture into areas that we haven’t gone before, or nobody has gone before, and to do so collaboratively.”