Targeting senescent cells immune evasion could lead to the development of a new class of senolytic drugs.

Senescent cells have emerged in the past decades as key contributors to pathologies with a chronic inflammatory component such as osteoarthritis, atherosclerosis, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (Childs BG; 2017). Senescent cells are characterised by irreversible cell cycle arrest, resistance to apoptosis and a senescence associated secretory phenotype (SASP). Interleukin-1alpha, -6 and -8 are major mediators of the SASP and are believed with other mediators to contributes to the spread of senescence to neighbouring cells by the so-called senescence-induced bystander effect.

 Recent clinical trials using senolytic drugs such as Dasatinib (pan tyrosine kinase receptor inhibitor) and Quercetin (plant flavonoid with a broad range of biological effects) provided encouraging results in the treatment of idiopathic pulmonary fibrosis (Justice NJ et al., 2019) and diabetic kidney disease (Hickson LJ et al., 2019). However, so far, senolytic drugs suffer from a lack of specificity and are not devoid of adverse effect (e.g., gastrointestinal discomfort, headache for the Dasatinib/Quercetin combination therapy).

 In the June 2019 issue of Nature, Pereira BI et al., published data suggesting that senescent cells evade immune clearance by Natural Killer (NK) and CD8+ T cells by increasing their expression of HLA-E. Using in vivo as well as in vitro approaches, the authors showed that senescent cells increase their expression of HLA-E in an autocrine fashion through SASP derived cytokines. They also showed that senescent cells HLA-E engagement with the inhibitory receptor NKG2A expressed by NK and CD8+ T cells was responsible for their immune evasion. Importantly, blocking this interaction boosted the immune response against senescent cells, and provide thereby a new strategy for the development of senolytic drugs.

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