Scientists identify immune targets for chemotherapy-resistant breast cancers

Scientists identify immune targets for chemotherapy-resistant breast cancers

Scientists have identified immune cell types that could be targeted to develop specific immunotherapies for chemotherapy-resistant breast cancer.

Researchers from King's College London and the Institute of Cancer Research, London, with support from Breast Cancer Now, have carried out a detailed study of the various immune markers in tumor tissues and blood samples from early-stage breast cancer patients whose cancer did not respond to chemotherapy given to them before surgery.

The study, published today in Clinical Cancer Research, a journal of the American Association for Cancer Research, provides insight into the function of immune cells in patients with chemotherapy-resistant breast cancer. While chemotherapy may not kill cancer cells in these high-risk patients, immunotherapy, a type of treatment that helps the immune system attack cancer cells, may provide benefit.

To study the immune environment surrounding these chemotherapy-resistant tumors, researchers used multiple and novel complementary technologies to examine proteins and genes in both breast cancer tissue before and after treatment. They also measured how 1,330 cancer and immune-related genes in cancer tissues were affected by chemotherapy.

They found that chemotherapy-resistant cancer cells had very few immune cells around them, but chemotherapy caused changes in several immune cell types. In particular, they found an increase in the number of “innate” (first responder) cells such as neutrophils and natural killer (NK) cells. NK cells help the body fight infections and cancer. However, the analysis found that the increased NK cells in patients with chemotherapy-resistant disease did not exhibit cytotoxic activity - the "killing instinct."

The researchers also found that immune-related genes associated with NK cells are linked to cell inhibition or exhaustion, meaning NK cells are unable to fight cancer cells. These new insights into NK cell behavior could be used to develop specific immunotherapies for these high-risk patients. This would need to be investigated in future clinical trials.

These results also show that blood monitoring during chemotherapy may help predict chemotherapy response early and potentially allow tailored treatment before surgery.

Chemotherapy resistance in early-stage, aggressive breast cancer is a major reason the cancer grows back after treatment and is a significant contributor to people not surviving their disease. To find the right targets for drug development, it is important to have a deep understanding of the complex mechanisms that allow some cancer cells to resist treatment, then hide from our immune system, and only resurface later when they are more difficult to eradicate.

Our work has identified several cell types that would be worth studying further to understand how they interact with the resistant cancer cell and how we can optimize this to our advantage. I look forward to further investigating these results.”

Dr. Sheeba Irshad, lead author, Clinician Scientist at Cancer Research UK, King's College London

Professor Andrew Tutt, director of the Breast Cancer Now Toby Robins Research Center at the Institute of Cancer Research, London, and the Breast Cancer Now Research Unit at King's College London, said: "Great progress has been made in the use of immunotherapies to treat multiple diseases." However, we need to do a better job of unlocking their potential for breast cancer patients.

"This exciting work expands our understanding of the interaction between cancer cells and the immune system during treatment and why existing treatments work well in some patients but not others. I hope this research will help us improve the immune response against cancer." Breast cancer, particularly in patients whose cancer has not responded well to chemotherapy.”

Dr. Kotryna Temcinaite, senior research communications manager at Breast Cancer Now, said: “With an estimated 35,000 people living with incurable secondary (metastatic) breast cancer in the UK, it is vital we develop smarter and more effective treatments to ensure fewer people hear the devastating news.” News that the disease has returned and spread to other parts of the body. This exciting early-stage research, funded in part by Breast Cancer Now, is helping to lay the foundation for discovering a way to attack breast cancer cells that resist chemotherapy. We hope that based on these findings, scientists will ultimately be able to develop immunotherapy treatments that may potentially help more people survive breast cancer."

Source:

King's College London

Reference:

Gazinska, P., et al. (2022) Dynamic changes in NK, neutrophil and B cell immunophenotypes relevant in early breast cancer at high risk of metastasis after neoadjuvant chemotherapy. Clinical cancer research. doi.org/10.1158/1078-0432.CCR-22-0543.