Washington, December 17
Researchers have found a reason why residual breast cancer survives chemotherapy and does not respond to immunotherapy, according to a study.
Scientists at Tulane University in the United States have discovered for the first time how breast cancer persists after chemotherapy and why immunotherapies designed to eliminate remaining tumor cells by boosting the immune system are not effective against such cancers.
Most forms of breast cancer are highly treatable, especially when detected early. But the last borderline cases remain the deadliest and hardest to treat. The last borderline cases refer to those forms of cancer that cannot be treated with hormonal or targeted therapies and that do not respond to chemotherapy.
According to the study, the process of surviving chemotherapy triggers a program of immune checkpoints, or regulators of the immune system. These checkpoints protect breast cancer cells from being attacked by the immune system.
This process thus creates a “kill the mole” problem for immunotherapy drugs called checkpoint inhibitors, which can kill tumor cells expressing one checkpoint but not others that have multiple checkpoints, according to a study published in the journal Nature Cancer.
“Breast cancer does not respond well to immune checkpoint inhibitors, but it has never been understood why,” said corresponding author James Jackson of Tulane University.
“We found that they evade immune clearance by expressing a complex, redundant program of control genes and immunomodulatory genes.
“After chemotherapy, the tumor completely changes into a thing that’s basically built to block the immune system,” Jackson said.
The researchers studied the process in mouse and human breast tumors and identified 16 immune checkpoint genes that code for proteins designed to inactivate cancer-causing T-cells, the study said.
“We are among the first to actually study a tumor that survives chemotherapy, which is called residual disease, to see what immunotherapy targets are expressed,” said the study’s first author, Ashkan Shahbandi.
Instead of dying after treatment, the tumors that respond worst to chemotherapy enter a dormant state called cellular senescence.
According to the researchers, they found two major populations of senescent tumor cells, each expressing different immune checkpoints activated by specific signaling pathways. They showed that the expression of immune evasion programs in tumor cells requires both chemotherapy to induce a senescent state and signals from non-tumor cells.
The researchers then tested a combination of drugs targeting these different immune checkpoints. While response could be improved, these strategies failed to fully eradicate most tumors, the study said.
“Our findings reveal the challenge of eliminating residual disease populated by senescent cells that activate complex immune inhibitory programs.
“Breast cancer patients will need rational, personalized strategies that target specific chemotherapy-induced checkpoints,” Jackson said.
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