Why Don’t Chemotherapy-Resistant Breast Cancers Respond to Immunotherapy?

According to an early study, when breast cancer cells survive chemotherapy, they develop immune checkpoints that shield the cells from immunotherapy medicines.

The research was published in the Dec. 8, 2022, issue of the journal Nature Cancer. Read the abstract of “Breast cancer cells survive chemotherapy by activating targetable immune-modulatory programs characterized by PD-L1 or CD80.”

Keytruda (chemical name: pembrolizumab) is a type of immunotherapy medicine called an immune checkpoint inhibitor. Keytruda is used to treat both early-stage and advanced-stage triple-negative breast cancer.

Jemperli (chemical name: dostarlimab-gxly) is another immune checkpoint inhibitor used to treat mismatch repair deficient (dMMR) advanced-stage breast cancer that has grown during or after treatments.

Immune checkpoints are proteins in your body that help your immune system tell the difference between your own cells and foreign invaders, such as harmful bacteria or cancers. Cancer cells sometimes find ways to use these immune checkpoint proteins as a shield to avoid being identified and attacked by the immune system.

Immune checkpoint inhibitors target these immune checkpoint proteins and help the immune system recognize and attack cancer cells. PD-1 is a type of checkpoint protein found on T cells, which are immune system cells that roam throughout the body looking for signs of disease or infection. PD-L1 is another checkpoint protein found on many healthy cells in the body. When PD-1 binds to PD-L1, it stops T cells from killing a cell.

Still, some cancer cells have a lot of PD-L1 on their surfaces, which stops T cells from killing these cancer cells. An immune checkpoint inhibitor medicine that stops PD-1 from binding to PD-L1 allows T cells to attack the cancer cells.

Breast cancers that don’t respond to chemotherapy also don’t respond well to immune checkpoint inhibitors. In this study, the researchers wanted to understand why, so they looked at human breast cancer cells that had been treated with chemotherapy. The researchers also looked at how breast cancer cells responded to chemotherapy and immune checkpoint inhibitors in mice.

They found that when breast cancer cells don’t respond to chemotherapy, they become dormant — asleep in a sense — instead of dying from the chemotherapy. Scientists call this dormant state cellular senescence. 

The researchers identified two types of dormant breast cancer cells. Each type expressed different immune checkpoints that allowed the cancer cells to deactivate T cells.

“Breast cancers don’t respond well to immune checkpoint inhibitors, but it has never really been understood why,” James Jackson, PhD, associate professor of biochemistry and molecular biology at Tulane University School of Medicine, said in a statement. “We found that they avoid immune clearance by expressing a complex, redundant program of checkpoint genes and immune modulatory genes. The tumor completely changes after chemotherapy treatment into this thing that is essentially built to block the immune system.”

The researchers treated the two types of dormant breast cancer cells with drugs that targeted the immune checkpoints the cells were expressing. Although some of the cells responded, most did not.

“Our findings reveal the challenge of eliminating residual disease populated by senescent cells that activate complex immune inhibitory programs,” Dr. Jackson said. “Breast cancer patients will need rational, personalized strategies that target the specific checkpoints induced by the chemotherapy treatment.”

This is an early study and the results may not be applicable to people diagnosed with breast cancer for a number of years. Still, it does offer important information on how chemotherapy can change breast cancer cells. It also offers more information on why immunotherapy may not work after chemotherapy.

Future studies are likely to develop immunotherapy medicines that target immune checkpoints other than PD-L1.

Learn more about immunotherapy.