ACS Research Highlights

Some Natural Killer Cells Aid & Abet Triple-Negative Breast Cancer

An ACS-funded researcher learns how cells that typically kill infected and diseased cells switch sides in the tumor microenvironment to help TNBC grow. 

The Challenge

Compared to other subtypes of breast cancer, triple-negative breast cancer (TNBC) grows faster and is more likely to spread and recur. It is more common in women younger than age 40, who are Black, or who have a BRCA1 genetic mutation.

It’s called triple-negative breast cancer because the cancer cells in TNBC don’t have receptors for the hormones estrogen (ER) or progesterone (PR). Plus, TNBC cells make very little or none of the protein called HER2 (human epidermal growth factor). That means all 3 biopsy tests to check for these hormones and the HER2 protein come back “negative.” 

The lack of these receptors is a key reason TNBC is hard to treat. Hormone therapy is one of the most effective treatments for breast cancer, but it requires ER or PR receptors to work. Anti-HER2 drugs are another effective treatment for some types of breast cancer, but they also won’t work because the TNBC cells don’t have enough HER2 for the drugs to bind to and block the tumor’s growth.  

The fact that these tumors vary widely between patients, as well as in their cellular makeup, only adds to the challenges of developing effective treatments.

Potential drug targets in the tumor microenvironment. 
As researchers look for potential drug targets, they’re studying the microenvironments of TNBC tumors. The tumor microenvironment consists of a variety of cells, a meshwork of fibers, and blood vessels that surround a tumor.

Compared to the microenvironment of other subtypes of breast cancer, the microenvironment around a triple-negative tumor has a large number of immune cells. These nearby immune cells seem to help the tumor grow and become resistant to drugs.

The presence of immune cells in the microenvironment suggests that  immunotherapy may be effective against TNBC. However, in clinical trials, immunotherapies aren’t working very well against TNBC.

Glossary for Nonscientists

Featured Term:
Cancer stem cells

Cancer stem cells are small subpopulation of tumor cells in many types of cancers. They make up about 1% to 3% of all cells in a tumor. They seemingly multiply indefinitely, are resistant to chemotherapy, and are thought to be responsible for relapse after therapy. Cancer stem cells can drive the development and progression of a tumor including generating cells that spread to other organs and tissues in the body in the process of metastasis. 

Natural killer (NK) cells. These are white blood cells that are supposed to destroy infected and diseased cells including cancer. However, researchers have found that in certain types of cancer, like in the lung and kidney, a subset of immature NK cells actually help cancer cells grow, instead of killing them. Consequently, this could make NK cells a potential drug target for these cancers. But until recently, NK cells have not been well studied for TNBC.

More in-depth studies of TNBC’s tumor microenvironment may help scientists discover new ways to treat this cancer.

The Research

American Cancer Society (ACS) research grantee, Rumela Chakrabarti, PhD, studies how cell changes in the breast lead to the development and progression of breast cancer. Her long-term goal is to help identify new combination therapies that will help reduce deaths from aggressive breast cancers, like TNBC.

Chakrabarti recently published a study in Science Translational Medicine that involved molecular and functional analyses of TNBC tumors in mice. Those experimental findings were validated by analyses of breast cancer tissues from women.

The extensive tumor variation and immune-rich tumor microenvironment of TNBC likely contribute to its growth. We found many immune cells in different aggressive types of TNBC.”

Rumela Chakrabarti, PhD

University of Miami

ACS Research Grantee

Study of mice with TNBC. The team found an increased number of NK cells in TNBC tumors in mice. They also identified a distinct subset of NK cells in the tumor microenvironment (known as Socs3highCD11b−CD27−) that was associated with both the growth of TNBC tumors and their spread (metastasis).

In mice, the NK cells in the subset are immature and have unique features, including:

  • A greatly reduced ability to kill cancer cells.
  • An increased ability to help a TNBC tumor develop and grow by activating cancer stem cells, which have been implicated in both the initiation and progression of this aggressive type of breast cancer.

The NK cells support cancer stem cell growth by increasing the rate of messages sent through the Wnt signaling pathway (a communication pathway between the tumor and the tumor microenvironment that has a role in both normal and tumor development). Wnt signaling can turn immune cells “on and off,” regulating the cell’s anticancer immune response, meaning the signals can help tumors grow or stop them from growing.

Chakrabarti and her research team also learned that depleting this subset of NK cells or blocking communication between these NK cells and the Wnt pathway slowed the tumor’s progression and spread.

Depleting NK cells also improved the efficiency of an immunotherapy drug and also improved chemotherapy against TNBC in mice.

“We observed a high number of NK cells in several aggressive TNBC mouse models. In contrast, these cells were reduced in ER+/PR+ mouse tumors. This suggests that NK cells in the tumor microenvironment may not occur in breast cancers that are positive for estrogen and progesterone receptors,” Chakrabarti says. 

“Our findings indicate that NK cells in the tumor microenvironment of TNBC are distinct – they’re partly immature and associated with increased metastases and the formation of new blood vessels that promote tumor growth,” she says.

Further studies with larger numbers of patients and their survival records are needed to confirm these findings.

Study of TNBC human tissue samples. When the scientific team analyzed tissue samples from women being treated for TNBC, their findings were similar to the ones they had with mice. They observed:

  • The TNBC tumor microenvironment had a higher number of immature subset of NK cells compared to the number in non-TNBC (ER+/PR+) patient samples.
  • A link between high numbers of the subset of NK cells in the sample and a poorer overall survival rate for TNBC.
  • Reducing the numbers of these NK cells or blocking the Wnt signaling, together with using either a specific immunotherapy (immune checkpoint inhibitor) or a specific chemotherapy drug, slowed the growth of the tumor.

Together, the researchers’ findings identify a population of immature and non-cytotoxic NK cells that promote the growth of TNBC instead of killing them.

That means these NK cells can be further studied to learn if they can help with diagnosis, treatment, or both. 

Why It Matters

The study provides insight into the paradox of how specific, immature NK cells don’t kill harmful cells as they do in the bloodstream, but instead lead to tumor growth in TNBC by activating Wnt signaling. The function of NK cells with cancer highly depends on how mature they are and where they are in the body and proximity to the tumor.

Chakrabarti’s discovery that reducing the numbers of this NK cell subset reduced the progression of tumors at both early and late stages suggests that targeting them may be helpful for preventing progression to an advanced stage.

More studies to identify additional features of these cells will help scientists develop more targeted treatments against TNBC.

“Our research shows promise for the use of combination therapy targeting this special subset of NK cells along with a specific immunotherapy or chemotherapy,” Chakrabarti says. “Our hope is that these new insights may lead to better treatments that improve and lengthen the lives of women with TNBC who currently face so many challenges.”