Washington: Researchers have found the reason why residual breast cancer survives chemotherapy and does not respond to immunotherapies, according to a study. Researchers from Tulane University in the United States have discovered for the first time how breast cancer persists after chemo and why immunotherapies designed to clear out the remaining tumour cells by revving up the immune system are not effective on such cancer.
Most forms of breast cancer are highly treatable, especially when detected early. But the last frontier cases remain the deadliest and the hardest to treat. Last frontier cases refer to those forms of cancer that cannot be treated with hormone or targeted therapies and that do not respond to chemotherapy.
According to the study, the process of surviving chemotherapy triggers a programme of immune checkpoints or regulators of the immune system. These checkpoints protect the breast cancer cells from being attacked by the immune system.
The process, thereby, creates a “whack-a-mole” problem for immunotherapy drugs called checkpoint inhibitors that may kill tumour cells expressing one checkpoint but not others that have multiple checkpoints, according to the study published in the Nature Cancer journal.
“Breast cancer does not respond well to immune checkpoint inhibitors, but it has never really been understood why,” said corresponding author James Jackson of the Tulane University.
“We found that they avoid immune clearance by expressing a complex, redundant programme of checkpoint genes and immune modulatory genes.
“The tumour completely changes after chemotherapy treatment into this thing that is essentially built to block the immune system,” Jackson said.
The researchers studied the process in mouse and human breast tumours and identified 16 immune checkpoint genes that encode proteins designed to inactivate the cancer-killing T-cells, the study said.
“We are among the first to actually study the tumour that survives post chemotherapy, which is called the residual disease, to see what kind of immunotherapy targets are expressed,” said the study’s first author, Ashkan Shahbandi.
The tumours that respond the worst to chemotherapy enter a state of dormancy called cellular senescence, instead of dying after treatment.
According to the researchers, they found two major populations of senescent tumour cells, each expressing different immune checkpoints activated by specific signalling pathways. They showed that the expression of immune evasion programmes in tumour cells required both chemotherapy to induce a senescent state and signals from non-tumour cells.
The scientists then tested a combination of drugs aimed at these different immune checkpoints. While the response could be improved, these strategies failed to fully eradicate the majority of tumours, the study said.
“Our findings reveal the challenge of eliminating residual disease populated by senescent cells that activate complex immune inhibitory programmes.
“Breast cancer patients will need rational, personalised strategies that target the specific checkpoints induced by the chemotherapy treatment,” Jackson said.
