Checkpoint blockade immunotherapy employs the usage of immune checkpoint inhibitors. These inhibitors block the immune system cells made proteins called checkpoints. Since checkpoints obstruct the immune responses from being too robust and prevent T cells from killing cancer cells, blocking the checkpoints facilitates T cells to kill cancer cells better. However, for > 80% of cases, this therapy has been ineffective. Hypoxia and its lead modifications in tumor cells are responsible for this therapy resistance.
Hypoxia enables cancer cells to evade the immune system resulting in therapy resistance. It was recently found that hypoxia induces increased expression of the BIRC2 gene in breast cancer and melanoma cells. BIRC2 inhibits cell "suicide," or apoptosis of cancer cells, and blocks the recruitment of T-cells and natural killer cells, thus allowing cancer cell survival.
The study revealed that the knockdown of BIRC2 lead to:
1. Enhanced expression of CXCL9, which is responsible for drawing T-cells and natural killer cells to the tumors.
2. More immunogenic tumors.
3. Sensitized melanoma and breast cancer to checkpoint blockade immunotherapy.
Thus, BIRC2 is one of the culprits in making breast cancer and melanoma cells resistant to immunotherapy, and using drugs that inactivate BIRC2 or other apoptosis inhibitors can improve the response to immunotherapy drugs.
Reference: Samanta, D., Huang, T. Y., Shah, R., Yang, Y., Pan, F., & Semenza, G. L. (2020). BIRC2 Expression Impairs Anti-Cancer Immunity and Immunotherapy Efficacy. Cell reports, 32(8), 108073. https://doi.org/10.1016/j.celrep.2020.108073
