Nature Cancer has found why immunotherapy is ineffective for the most difficult breast cancers to treat

Due to advances in cancer treatment, most forms of breast cancer are highly treatable, especially when
detected early.

But the last frontier cases — those that can't be treated with hormones or targeted therapies and don't respond to chemotherapy — remain the deadliest and hardest to treat
.
Researchers at Tulane University have first discovered how these cancers persist after chemotherapy and why they don't respond well
to immunotherapies designed to remove remaining tumor cells by speeding up the immune system.
The process of surviving chemotherapy triggers an immune checkpoint program that protects breast cancer cells from different attacks
by the immune system.
According to a new study published in the journal Nature Cancer, this creates a "whack-a-mole" problem for an immunotherapy drug called checkpoint inhibitors, which may kill tumor cells that express one checkpoint instead of other tumor cells
with multiple checkpoints.

"Breast cancer doesn't respond well to immune checkpoint inhibitors, but it never really understands why," said corresponding author Dr.
James Jackson, "and we found that they avoid immune clearance
by expressing a complex, redundant checkpoint gene and immunomodulatory gene program.
" Tumors completely change into this thing after chemotherapy, essentially to block the immune system
.
”

The researchers studied this process in mouse and human breast tumors and identified 16 immune checkpoint genes that encode proteins designed to inactivate cancer-killing T cells
.

"We are the first to actually study tumors that survive chemotherapy, which is known as residual disease, to see which immunotherapy targets are expressed," said Ashkan Shahbandi, MD/doctoral student in Jackson's lab, lead author of the study
.
Tumors that respond the least to chemotherapy go into a dormant state after treatment — called cellular senescence — rather than die
.
The researchers identified two main 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 aging states and signals
from non-tumor cells.

They tested combinations
of drugs that targeted these different immune checkpoints.
While response can be improved, these strategies have failed to completely eradicate most tumors
.

Jackson said: "Our findings reveal the challenge of
eliminating residual diseases made up of senescent cells that activate complex immunosuppressive programs.
" "Breast cancer patients will need reasonable, individualized strategies to target specific checkpoints
caused by chemotherapy.
"