Checkpoint Inhibition Improves Clearance of Senescent Cells

Immune checkpoint inhibition, such as via targeting PD1, is used to fire up the immune system to attack cancer, temporarily disabling some of the natural mechanisms intended to prevent immune cells from running amok. In the case of cancer, this is intended to overcome the abuse of immune checkpoints by cancerous tissue, one of the many strategies by which an established tumor suppresses or co-opts the immune system. But does inhibition of immune checkpoints improve other aspects of immune function? Apparently so, as in today's open access paper, researchers present evidence for a reduced burden of senescent cells following checkpoint inhibition.

Interestingly, it is unclear as to whether the improvement of measures of health in mice is as much a matter of reducing the harmful pro-inflammatory senescence-associated secretory phenotype (SASP) as it is resulting from clearance of senescent cells. Checkpoint inhibitors, at least PD-L1, appear to be involved in generation of the SASP, as cells lacking that gene produce a more muted SASP.

While this is interesting research, checkpoint inhibition seems unlikely to be a viable addition to the range of senolytic therapies presently under development, however. If one looks at the clinical trial data for established checkpoint inhibitors used to treat cancer, there appears to be something like a 7% chance of lasting complications resulting from treatment. That list of problems includes the possibility of developing forms of autoimmunity - immune checkpoints exist for a reason. The cost-benefit equation for a cancer that will go on to kill you, and for which the alternative treatments are worse, is somewhat different to that for an increased burden of senescent cells that will kill you very much more slowly, and for which the range of alternative treatments come with next to no risk of lasting side-effects.

Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes

The accumulation of senescent cells is a major cause of age-related inflammation and predisposes to a variety of age-related diseases. However, little is known about the molecular basis underlying this accumulation and its potential as a target to ameliorate the ageing process. Here we show that senescent cells heterogeneously express the immune checkpoint protein programmed death-ligand 1 (PD-L1) and that PD-L1+ senescent cells accumulate with age in vivo. PD-L1- cells are sensitive to T cell surveillance, whereas PD-L1+ cells are resistant, even in the presence of senescence-associated secretory phenotypes (SASP).

Single-cell analysis of p16+ cells in vivo revealed that PD-L1 expression correlated with higher levels of SASP. Consistent with this, administration of programmed cell death protein 1 (PD-1) antibody to naturally ageing mice or a mouse model with normal livers or induced nonalcoholic steatohepatitis reduces the total number of p16+ cells in vivo as well as the PD-L1+ population in an activated CD8+ T cell-dependent manner, ameliorating various ageing-related phenotypes.

These results suggest that the heterogeneous expression of PD-L1 has an important role in the accumulation of senescent cells and inflammation associated with ageing, and the elimination of PD-L1+ senescent cells by immune checkpoint blockade may be a promising strategy for anti-ageing therapy.


If the half life of the checkpoint inhibitor was shortened (and dose increased?), perhaps there wouldn't be too much long term immune memory trained or other side effects per useful immune activity.

Also, it'd be interesting if something secondary could tip the scales of immune system target priorities, even if fuzzy.

Posted by: Tronson at November 14th, 2022 9:59 PM
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