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

Abstract

The accumulation of senescent cells is a major cause of age-related inflammation and predisposes to a variety of age-related diseases¹. 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.