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A rendering of T-cells (blue and red) attacking a cancer cell (purple). (Meletios Verras/iStock)

BCRF-Supported Study Reveals How Tumor Cells Use Novel Strategy to Resist Immunotherapy

Researchers hope to improve the immune response to T-cell and personalized CAR T-cell targeted therapies

A study led by BCRF investigator Dr. Joaquín Arribas and published in Nature Communications unveiled a strategy breast cancer cells use to resist immune attack.

Immunotherapy harnesses the power of a patient’s immune system to target and kill cancer cells. T-cells, a type of immune cell, recognize and bind to cancer cells, causing a cascade of cell signaling events that lead to cancer cell death. However, T-cells are not always efficient at recognizing cancer cells, which can adapt to evade immune attack. Since little is known about the mechanism that allows cancer cells to evade immune response, researchers are investigating this question and developing immunotherapies that enhance T-cell function.

Dr. Arribas’ recent findings build on his previous work, whereby he showed that immune cells could be redirected to accurately target cancer cells with high amounts of the HER2 protein, a known driver in 20 to 25 percent of breast cancers. This new finding opens up the possibility that researchers could block the process by which these breast cancer cells evade attack and thereby improve the effectiveness of immunotherapies for the disease.

Engineering more effective T-cells

To enhance T-cell function, researchers engineer T-cell bispecific antibodies and CAR T-cells in the laboratory.

Bispecific antibodies utilize a unique Y-shaped antibody structure to enhance the tumor cell–killing effectiveness of T-cells by bringing the tumor cell into proximity of the T-cell. One arm of the Y binds to the T-cell and the other arm binds to the tumor cell. Once closer together, the T-cells can kill tumor cells more efficiently.

The other method of enhancing T-cell effectiveness is called CAR T-cell technology, a truly personalized immunotherapy that involves reprogramming a patient’s own T-cells to zero in on their specific cancer. T-cells are isolated from a patient’s blood and manipulated in the laboratory to produce specific surface proteins to create a chimeric antigen receptor (CAR) T-cell. Once injected back into the patient, CAR T-cells can multiply and bind to cancer cells expressing the specific antigen. A single CAR T-cell can target and kill more than 1,000 cancer cells.

The first CAR T-cells were developed and approved to treat certain blood cancers. Scientists are finding ways to apply this technology to solid tumors, including breast cancer. In fact, specific CAR T-cells that target the HER2 protein on some breast cancer cells have already been developed.

How HER2-positive cancer cells evade immune attack

In a previous study, Dr. Arribas and his colleagues showed that a HER2 T-cell bispecific antibody could successfully guide T-cells to HER2 expressing cancer cells. The results reported in the team’s current study add to this observation and show that even though the HER2 T-cells effectively target the HER2-positive cancer cells, the cancer cells can still evade death. The team probed further to determine exactly how these cancer cells were able to evade immune attack by performing a series of experiments with HER2-positive cancer cells treated with T-cell bispecific antibodies or HER2 targeting CAR T-cells.  They found that the cancer cells utilized a novel mechanism to evade immune attack—these cells could switch off a key pathway in T-cell activation called interferon-gamma.

What this means for patients

Enhancing T-cell activity, whether by bispecific antibodies or more personalized CAR T-cell technology, holds promise for treating breast cancer. These discoveries from Dr. Arribas and his colleagues provide valuable clues that may be exploited to improve the effectiveness of these therapies, which are not yet used to treat breast cancer.

In continuing research, the team will investigate other mechanisms by which cancer cells can evade targeted T-cells. In addition, they will also develop methods to identify patients who are most likely to benefit, while continuing to work on other ways to improve the effectiveness of immunotherapy for more patients.

Additional resources:

Video: Explaining Bispecific Molecules

Video: A Look at How CAR-T Cell Therapy Works

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