Thanks to advances in cancer treatment, most forms of breast cancer are highly treatable, especially when caught early.
But terminal cases—those that cannot be treated with hormones or targeted therapies and do not respond to chemotherapy—remain the most deadly and difficult to treat. Tulane University researchers have discovered for the first time how these cancers persist after chemo and why they do not respond well to immunotherapies designed to kill remaining tumor cells by revitalizing the immune system.
Chemotherapy survival triggers a program of immune checkpoints that protect breast cancer cells from various lines of attack by the immune system. This creates a “hack-a-mole” problem for immunotherapy drugs called checkpoint inhibitors that can kill tumor cells that express one checkpoint but not others with multiple checkpoints, according to a new study published in the journal Nature Cancer.
“Breast cancer does not respond well to immune checkpoint inhibitors, but it has never been understood exactly why,” said corresponding author James Jackson, PhD, associate professor of biochemistry and molecular biology at Tulane University School of Medicine. “We discovered that they evade immune clearance by expressing a complex, redundant program of checkpoint genes and immune modulatory genes. After chemotherapy treatment, the tumor is completely transformed into something that is essentially designed to block the immune system.
The researchers studied the process in mouse and human breast tumors and identified 16 immune checkpoint genes that encode proteins designed to deactivate cancer-killing T-cells.
“We are among the first to study tumors that survive after chemotherapy, known as residual disease, to see what types of immunotherapy targets are expressed,” said study first author Ashkan Shahbandi, an MD/PhD student. Jackson’s Laboratory.
Tumors that respond worst to chemotherapy enter a state of dormancy—known as cellular senescence—rather than dying after treatment. The researchers found two major populations of senescent tumor cells, each expressing different immune checkpoints activated by specific signaling pathways. They show that expression of immune evasion programs in tumor cells requires both chemotherapy to induce a senescent state. and Signals from non-tumor cells.
They tested combinations of drugs targeting these different immune checkpoints. While response can be improved, these strategies fail to completely eradicate most tumors.
“Our findings reveal the challenge of eliminating residual disease populated by senescent cells that activate complex immune inhibitory programs,” Jackson said. “Breast cancer patients need rational, individualized strategies targeting specific checkpoints induced by chemotherapy treatment.”
The full study is available at https://www.nature.com/articles/s43018-022-00466-y.
Breast cancer cells survive chemotherapy by activating immune-modulatory programs characterized by PD-L1 or CD80.
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The authors declare no competing interests.
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