Removing Senescent Cells Makes Chemotherapy More Effective
Cellular senescence is protective against cancer, at least initially. When cells become senescent due to potentially cancer-inducing damage, shutting down replication and secreting pro-inflammatory signals reduces the risk of cancer and attracts the immune system to clear out other potentially cancerous cells that have not become senescent. When senescent cells linger in larger numbers, however, they begin to aid cancer by changing the environment into one that favors the growth of cancerous tissue. Thus clearing senescent cells in conjunction with traditional cancer treatments is more effective for patients than the treatment on its own. Additionally, the established approaches of chemotherapy and radiotherapy produce a lasting burden of senescent cells in the course of killing the cancer. This harms patients, increasing their risk of age-related disease and reducing life expectancy, but senolytic therapies to clear those senescent cells may remove this well-established cost to successful cancer treatment.
Cancer treatments, including chemotherapy, in addition to killing a large number of tumour cells, also result in the generation of senescent tumour cells. While senescent cells do not reproduce, they do, unfortunately, generate a favourable environment for the expansion of tumour cells that may have escaped the effects of the chemotherapy and eventually result in tumour regrowth. Researchers have described how cancer cells that have become senescent after chemotherapy activate the PD-L2 protein to protect themselves from the immune system while recruiting immune suppressor cells. The latter creates an inhibitory environment that impairs the ability of lymphocytes to kill cancer cells.
Based on these findings, scientists wondered what would be the effect of inactivating PD-L2. Interestingly, senescent cells lacking PD-L2 are rapidly eliminated by the immune system. This intercepts the capacity of senescent cells to create an immunosuppressive environment and, as a result, lymphocytes retain their full capacity to kill those cancer cells that may have escaped the effects of chemotherapy. "By blocking PD-L2 in mouse models, we have seen that chemotherapy is more effective against cancer. This finding paves the way to consider the use of a potential PD-L2 inhibitor as an adjuvant in the treatment of this disease."
This both validates the "senesce and kill" strategy and takes it in a whole new direction (eg, highlighting PD-L2 relevence in persistence of immunosuppressive chronic senescence, validating anti-PD1 and anti-PDL2 as senolytics across therapy-induced senescence models). EXCELLENT paper. Thank you for bringing it to our attention.