Cellular senescence: Immunosurveillance and future immunotherapy
Burton DGA, Stolzing A. Cellular senescence: Immunosurveillance and future immunotherapy. Ageing Res Rev. 2018 May;43:17-25. doi: 10.1016/j.arr.2018.02.001. Epub 2018 Feb 7. PMID: 29427795.
Introduction
Cellular ageing is a result of gradual accumulation of damage over time while cellular senescence is a programmed change in cell state and a permanent inhibition of growth. Senescent cells gain new functions, but aged cells do not.
Senescence induction is the programmed response following DNA damage response (DDR) triggered by stressing stimuli.
One of the main phenotypes of senescent cells is the senescence-associated secretory phenotype in which the cells secrete pro-inflammatory cytokines, growth factors and proteases.
Immune response
The DDR during the induction of senescence induces an altered secretome that attracts and activates immune cells and upregulates the expression of NKG2D ligands on senescent cells allowing them to be recognized by immune cells.
The reactivation of p53 in p53-deficient tumours promoted the induction of senescence which was associated with the activation of the innate immune system leading to tumour clearance. Clearance of senescent cells in fibrotic livers prevented excess fibrosis.
NK mediated killing depended on granule exocytosis and mice with defects in granule exocytosis accumulated senescent cells. There are cell receptors that are upregulated after senescence induction to allow identification by natural killer cells.
Senescent cells also release factors that promote macrophage polarisation towards a tumour-inhibiting M1 state capable of targeting senescent cells.
Immunosuppressive response
The senescence-mediated immune response can be immunosuppessive and tumour promoting. This may be dependent on the genetic background of the cells and the mode of senescence induction as well as whether the cells have persisted in senescence and undergone changes associated with a chronic response rather than a beneficial acute response. A chronic senescence response can promote age-related inflammatory disease.
Senescence of immune cells
The senescence of immune system cells can lead to immune suppression, elevated inflammation, accumulation of other senescent cells and immunosenescence which is the ageing of the immune system.
Astrocytes
β-amyloid can trigger cell senescence in astrocytes which could increase the risk of sporadic AD. Genes involved in neuronal development and differentiation were down-regulated in senescent astrocytes.
Immunotherapy targeting senescent cells
The removal of senescent cells could be a potential therapy for senescence associated ageing diseases like AD. However, removing acute senescent cells could be problematic and prevent normal functioning like wound healing and tumor suppression.
Senolytics that use the immune system to target senescent cells may not work if the immune system has itself undergone senescence.