Triple Negative: Communication with Immune System
Anna Zolkiewska, professor in biochemistry & molecular biophysics, studies breast cancer. Not all breast cancers are the same. She focuses on one sub-type called triple negative. White blood cells poorly kill this sub-type because it tries to avoid the anti-tumor immunity by forming an immunosuppressive tumor environment and often doesn’t respond to new immunotherapies.
Zolkiewska studies how cancer cells communicate with the immune system. Treatments for cancer, especially breast cancer, can be very toxic, and radiation, chemotherapy, and other harsh treatments give people unpleasant side effects. Immunotherapies, on the other hand, are usually well tolerated and represent a breakthrough in the treatment of many cancers. But triple negative breast cancer is different. Zolkiewska said: “The problem is that triple negative breast cancer cells know how to evade the immune system and how to avoid being killed by the immune cells.”
The Zolkiewska laboratory focuses on understanding which genes and proteins are responsible for the immunosuppressive tumor environment in triple negative breast cancer. They try to boost the immune system so it will not be fooled by cancer cells. They utilize cellular and mouse studies that examine immune checkpoints, proteins that keep the immune system under control.
The immune checkpoints are a “hot” topic in oncological science. In 2018, the Nobel Prize in Physiology and Medicine was awarded to Dr. James Allison and Dr. Tasuku Honjo for developing the immune checkpoint blockade therapy. Immune checkpoints are negative regulators of the immune system. The Nobel Prize winners demonstrated that immunotherapy with immune checkpoint inhibitors is one way to boost the immune system – after the therapy, immune cells can recognize and kill tumors.
In the Zolkiewska laboratory, researchers transplant mouse breast cancer cells into the mammary glands in mice, where cancer normally grows. The type of tumors that arise do not respond to immune checkpoint inhibitor therapy. So, Zolkiewska tries to introduce some genetic changes to cancer cells before they are transplanted to mice. She focuses on a large class of proteins found on the surface of cancer cells, called ADAMs. Recently, her group found that disabling one ADAM gene, ADAM12, in cancer cells makes a big difference in how tumors respond to the immunotherapy. ”We deleted the ADAM12 gene in cancer cells and injected these cells into mammary glands in mice. As control, we injected cancer cells which had an intact ADAM12 gene. We found that mice injected with cells lacking ADAM12 responded to the checkpoint inhibitor therapy with tumor shrinkage. In contrast, mice injected with control cancer cells did not respond to the therapy at all.”
This work has been recently (December 2022) published in Oncoimmunology, 2023, Vol 12, No. 1, 2158006. The title of their article is “ADAM12 abrogation alters immune cell infiltration and improves response to checkpoint blockade therapy in the T11 murine model of triple-negative breast cancer. These results may have direct implications for future treatments. The Johnson Cancer Research Center (JCRC) helped with the research described in the paper. “It is very expensive to do genetic manipulations in animal models, and these studies were facilitated by JCRC here at K-State. Without the support we received, this research would not have been possible.”