Female patient undergoing mammography test in hospital.

Triple negative breast cancer (TNBC) is present in about 12% of breast cancer patients. This cancer is characterized by breast cancer cells that lack three surface cell receptors that are found in other breast cancers, and it is typically more aggressive and more likely to relapse. Currently, there are no targeted therapies for triple negative breast cancer.

Immunotherapy is designed to harness the power of a patient?s immune system to fight off cancer cells. ?It is used for a variety of cancers, including triple negative breast cancer, but its efficacy has been limited, especially in a certain subgroup of triple negative breast cancer that is known as ?claudin- low? breast cancer. ?A new study published in the Journal of Clinical Investigation is shedding some light on why claudin-low breast cancers do not respond to immunotherapy, and what can be done to solve it.

Claudin-Low Breast Cancer
Claudin-low breast cancer was first discovered in 2007, and it is characterized by a low expression of claudins 3, 4 and 7, occuldin and E-cadherin, which are genes that are involved in tight junctions and epithelial cell adhesion. They account for 7-14% of all invasive breast cancers, typically show high levels of genomic instability, and, unfortunately, are associated with a poor prognosis. [1]

Interestingly, claudin-low cancers show an elevated presence of immune cells in and near the tumor. With this heightened number of immune cells, researchers would expect that immunotherapy would be more effective, but quite the opposite has been revealed.

This immunotherapy resistance in claudin-low tumors has been witnessed in other cancers as well. A recent study published by The American Society for Clinical Investigation revealed that claudin-low bladder cancers were showing gene expression patterns that were consistent with those seen during active immunosupression. [2]

Researchers at UNC Lineberger Comprehensive Cancer Center?are revealing explanations for this phenomenon in claudin-low triple negative breast cancers. ?Their findings in gene expression analysis show that during immunotherapy, these tumors are not being flooded with immune cells that attack cancer, rather, they are showing a high concentration of regulatory T-cells- a type of immune cell that actually suppresses the body?s defenses. They concluded that s a chemical signal to attract regulatory T-cells is being released from these claudin-low tumors.

In this study, researchers used immune checkpoint inhibitory antibodies against cytotoxic T lymphocyte, and found that tumor growth control was ineffective. A large portion of the?tumor-infiltrating lymphocytes found were regulatory T-cells, which after being studied, showed ability to affect T cell responses.

In attempt to combat this immunosupression and clear the path for immunotherapy drugs, researchers tested an investigational approach that would deplete the presence of regulatory T-cells in conjunction with a checkpoint inhibitor immunotherapy.

What they have found is that this combination did actually slow tumor growth. In order for this to happen, stringent regulatory T-cell depletion needed to occur in combination with the checkpoint inhibitor. In fact, when therapies that only modestly reduced regulatory T-cells were used, there were no delays in tumor growth.

These findings show a crucial part of why immunotherapy isn?t working in these cancers, and how it may potentially be solved.

“I think it’s important for us to try to start segregating out the types of tumors that don’t respond to these treatments at a much granular genomic level, and try to figure out new mechanisms to enhance the response rate to immunotherapy.” said Jonathan Serody, MD, UNC Lineberger member and the Elizabeth Thomas Professor in the UNC School of Medicine.

Researchers hope these findings will underscore the need to study cancers on a genomic level, in order to personalize immunotherapy for each patient?s individual needs.


Last editorial review: September 12, 2017

Featured Image: Patient undergoing mammography. Courtesy: ? 2017 Fotolia . Used with permission.

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