AI News, STEM Rising Blog
- On 20. august 2019
- By Read More
While it is true that the immune system declines in effectiveness with age, and there is good evidence for this to degrade its ability to destroy cancerous and senescent cells, some fraction of senescent cells nonetheless still manage to linger past their welcome even in a youthful physiology.
Given a suitable set of targets in the biochemistry of senescence, it may be possible to enable the immune system to target and destroy the persistent senescent cells that would otherwise manage to evade its attentions, thereby building the basis for a new class of senolytic therapies capable of producing rejuvenation in the old.
In mouse models of hepatocarcinoma and liver fibrosis, restoring p53 function enables senescent cells to be eliminated by natural killer (NK) cells in part via NKG2D detection, while oncogenic RAS-induced senescence of hepatocytes promotes immune responses involving CD4+ T cells, neutrophils, and macrophages that lead to SnC removal.
Notably, however, p53 and p16 are not required to trigger cellular senescence in human tissues/cells, and many senescence features are p53 or p16 independent, suggesting that additional mechanisms may regulate the interplay between SnCs and the immune system.
Despite evidence of immune surveillance and clearance of SnCs in mice, SnCs accumulate with age in patients and are found in inflamed and damaged tissues, premalignant lesions, and arrested tumors and after chemotherapy or radiotherapy.
We measured the expression of NKG2D-L MICA and MICB in tumor samples from 10 patients with prostate cancer before and after mitoxantrone (MIT) treatment, which we previously showed induces cellular senescence based on cell cycle arrest and SASP markers.
As a first model, we induced cellular senescence by DNA damage or replicative senescence in normal human fibroblasts expressing wild-type p53/p16, or inactivated p53 (p53-), or knocked-down p16 (p16-).
Our other observations in which cells arrested and senesced with high levels of p16 but low levels of NKG2D-Ls, led us to postulate that the induction of NKG2D-L expression by SnCs may depend on the DNA damage response (DDR) but not on cell growth arrest per se.
We found that the cell culture media of senescent fibroblasts and epithelial cells contained soluble NKG2D-L MICA and that the media from persistent SnCs contained markedly higher levels of soluble NKG2D-Ls compared with naive counterparts.
In conclusion, our data show how oncogenic and tumor-suppressive drivers of cellular senescence regulate surveillance processes that can be circumvented to enable SnCs to elude immune recognition but can be reversed by cell surface-targeted interventions to purge the SnCs that persist in vitro and in patients.
and since increasing numbers of B cells express NKG2D ligands in NKG2D receptor-deficient mice as they age, we propose that therapeutic interventions designed to increase cell surface presentation of NKG2D-Ls could be effective senolytic strategies to resensitize persistent SnCs to immune detection and rescue their clearance, whether in cancer or aging settings.
- On 23. januar 2021
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