4.8 Article

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

Journal

NATURE
Volume 611, Issue 7935, Pages 358-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41586-022-05388-4

Keywords

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Funding

  1. Imaging Core Laboratory, Institute of Medical Science, University of Tokyo
  2. FACS Core Laboratory, Institute of Medical Science, University of Tokyo
  3. AMED [JP22zf0127003h, JP20gm5010001s, JP20ck010655h, JP21gm6410014h, JP22gm1110009]
  4. MEXT/JSPS KAKENHI [JP20H00514, JP20K21497, JP19H05740, JP19H03431, JP20H04940, JP21H05044, JP22K1944]
  5. Princess Takamatsu Cancer Research Fund

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The accumulation of senescent cells is a major cause of age-related inflammation and diseases. This study reveals that senescent cells heterogeneously express the immune checkpoint protein PD-L1 and that PD-L1(+) cells accumulate with age. PD-L1(-) cells are sensitive to T-cell surveillance, while PD-L1(+) cells are resistant. The expression of PD-L1 correlates with higher levels of SASP.
The accumulation of senescent cells is a major cause of age-related inflammation and predisposes to a variety of age-related diseases(1). 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.

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