Achilles’ heel for immunotherapy identified in triple-negative breast cancer
In a recent study published in the journal Nature Communications, researchers from IGP show that the gene NEDD8 affects the capacity of cancer cells to develop resistance against immunotherapy. The findings could be used to develop more effective immunotherapies for the cancer form triple-negative breast cancer.
Immunotherapy has become an increasingly used strategy to treat cancer. One kind of immunotherapy is immune checkpoint blockade (ICB), which aims to block the cancer cells’ capacity to escape immune cells that could attack and kill them. ICB therapy has brought benefits to many cancer patients but patients with triple-negative breast cancer (TNBC) are less likely to enjoy long-term benefits of the therapy.
This is partly due to resistant mechanisms in the cancer cells. In the current study, the researchers discovered that the resistance gene NEDD8 has an important role in the development of ICB therapy resistance.
“We studied more than 19,000 genes and found that NEDD8 is the most prominent resistance gene that prevents TNBC cells to be attacked by immune cells. When the NEDD8 gene was cut out from mouse breast cancer cells, many tumours disappeared after ICB therapy,” says Irineos Papakyriacou, doctoral student in Yumeng Mao’s research group and first author of the study.
The researchers could also show that the TNBC cells had become more immunogenic, i.e. more prone to give rise to an immune response, when they lacked the NEDD8 gene.
“There is of course still much work to be done, but we believe that NEDD8 is a good target to maximize the depth and duration of immunogenicity in cancer patients when combined with immunotherapeutic drugs”, says Irineos Papakyriacou.
Another conclusion from the study was that substances that inhibit the protein encoded by the NEDD8 gene are not specific but also affect other pathways. Treatments with such substance should therefore be carefully optimized to avoid a negative impact on the immune system. The researchers will continue to investigate the mechanisms behind the function of the NEDD8 protein, with the aim to find innovative ways for optimal inhibition of this pathway.
“This exciting project has pushed our work outside the conform zone and we believe that a lot remains to be discovered about how NEDD8 can be used to improve cancer immunotherapy,” says Yumeng Mao who has led the study.