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

Teh-Wei Wang, Yoshikazu Johmura (), Narumi Suzuki, Satotaka Omori, Toshiro Migita, Kiyoshi Yamaguchi, Seira Hatakeyama, Satoshi Yamazaki, Eigo Shimizu, Seiya Imoto, Yoichi Furukawa, Akihiko Yoshimura and Makoto Nakanishi ()
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Teh-Wei Wang: Institute of Medical Science, University of Tokyo
Yoshikazu Johmura: Institute of Medical Science, University of Tokyo
Narumi Suzuki: Institute of Medical Science, University of Tokyo
Satotaka Omori: Institute of Medical Science, University of Tokyo
Toshiro Migita: Institute of Medical Science, University of Tokyo
Kiyoshi Yamaguchi: Institute of Medical Science, University of Tokyo
Seira Hatakeyama: Institute of Medical Science, University of Tokyo
Satoshi Yamazaki: Institute of Medical Science, University of Tokyo
Eigo Shimizu: Institute of Medical Science, University of Tokyo
Seiya Imoto: Institute of Medical Science, University of Tokyo
Yoichi Furukawa: Institute of Medical Science, University of Tokyo
Akihiko Yoshimura: Keio University School of Medicine
Makoto Nakanishi: Institute of Medical Science, University of Tokyo

Nature, 2022, vol. 611, issue 7935, 358-364

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05388-4

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