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Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes
Teh-Wei Wang 1, Yoshikazu Johmura 2 3, Narumi Suzuki 1, Satotaka Omori 1, Toshiro Migita 1, Kiyoshi Yamaguchi 4, Seira Hatakeyama 4, Satoshi Yamazaki 5 6, Eigo Shimizu 7, Seiya Imoto 7, Yoichi Furukawa 4, Akihiko Yoshimura 8, Makoto Nakanishi 9
...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.