Some cancer cells can deploy parallel mechanisms to evade immune system defenses and resist immunotherapy treatment, according to a new study from the Garvan Institute for Medical Research.
By suppressing the action of killer T cells and hindering the immune system’s ability to mark tumor cells for destruction, breast cancer cells can replicate and metastasize, they found researchers
We know that breast cancer usually does not respond well to immunotherapy, and we wondered if there is an intrinsic mechanism that allows breast cancer cells to escape the immune system.”
Ms Louise Baldwin, first author, PhD student in Associate Professor Alex Swarbrick’s laboratory at Garvan
The researchers used a technique called DNA barcoding, which tags cells with a known sequence and tracks the progression of tumor cells over time.
“We have shown that there are rare cancer cells that are able to escape the immune system and escape treatment with immunotherapy,” says Ms Baldwin.
The mechanisms could be used as potential targets for therapies, to prevent tumor cells from adapting and spreading. Another future application could be in prognosis, where high cell counts could indicate which patients might not respond to immunotherapy.
The new study is published in Nature Communications.
While immunotherapy is an effective treatment for many cancers, in some people their cancer cells evolve to overcome the immune system’s defenses. This process is known as immunoediting, where the interaction between tumor cells and immune cells causes many cancer cells to be destroyed by the immune system, but leaves some undetected, which continue to grow and spread .
The researchers used mouse breast cancer cells labeled with a known DNA “barcode,” a sequence that was passed down from one generation of cells to the next.
The barcode allowed the team to see where the most aggressive and resistant cells came from, as they could trace them back to the original cell to see if it had grown or shrunk.
“Lead author Dr Simon Junankar wanted to understand whether the resistance was adaptive, whether cancer cells help themselves and knit together, or whether they are pre-programmed to evade the immune system,” says Associate Professor Alex Swarbrick, head of laboratory and co-director of Dynamic. Program Cellular Ecosystems in Cancer in Garvan.
The team found that even before treatment, the cancer cells had diversified. “Some cells had already acquired the ability to evade immunity, meaning they have an innate ability to escape the immune system,” he says.
Cells seem to do this with parallel approaches. One way is to suppress the action of killer T cells, which would normally destroy harmful cells. The other is to reduce the expression of MHC1 on cells, which act as a flag for the immune system to recognize harmful cells.
“Most tumor cells disappear when the immune system is turned on, but a small proportion continue to grow and spread,” says Associate Professor Swarbrick.
“Tumors continue to evolve and diversify, and the action of the immune system or treatment such as chemotherapy is like pruning a tree: the cancer cells are exterminated, but the remaining branches of the tree continue to grow.”
The researchers also looked at the cells’ genetics, but found no associated genes, suggesting that epigenetics may be at play.
Source:
Garvan Institute of Medical Research
Journal reference:
Baldwin, LA, et al. (2022) DNA barcoding reveals ongoing immunoediting of clonal cancer populations during metastatic progression and response to immunotherapy. Communications of nature. doi.org/10.1038/s41467-022-34041-x.