A ganglioside-based senescence-associated immune checkpoint

Abstract

Senescent cells accumulate in aging tissues, and their elimination can favor healthy aging1-4. Therefore, therapeutic interventions targeting cellular senescence may be promising strategies for delaying or reversing a vast range of age-related diseases5. As cells of the immune system are responsible for senescent cell elimination6-11, a possible anti-aging and pro-healthspan treatment is the specific activation of the immune system to induce senescent cell clearance. However, whether this elimination is limited by an immune checkpoint leading to tolerance of senescence cells is currently unknown. Here, we show that cellular senescence, elicited by various stressors other than oncogenic activation, triggers immune escape toward natural killer (NK) cells, which may thus limit the use of anti-senescence immunotherapies. Moreover, using mass spectrometry, we reveal that senescent cells reshuffle their glycosphingosine composition, toward a marked increase in the ganglioside content, including the appearance of disialylated ganglioside GD3. This senescence associated GD3 overexpression results from transcriptional upregulation of the gene encoding the enzyme ST8SIA1, which is responsible for GD3 synthesis. The high level of GD3 leads to a strong immunosuppressive signal affecting NK cell-mediated immunosurveillance. In a mouse model of lung fibrosis, senescent cell-dependent NK cell immunosuppression is blunted by in vivo administration of anti-GD3 monoclonal antibodies leading to a clear anti-fibrotic effect. These results demonstrate that GD3 upregulation in senescent cells drives a switch from immune clearance toward immune tolerance of senescent cells. Therefore, we propose that GD3 level acts as a senescence-associated immune checkpoint (SIC) that regulates NK cell functions toward senescent cells. Thus, targeting GD3 with specific antibodies may be a promising strategy for the development of effective anti-senescence immunotherapies.

Cellular senescence and the host immune system in aging and age-related disorders

“…In co-culture experiments, silencing of HLA-E or NKG2A blockade sensitized senescent fibroblasts to elimination by these immune subtypes [ 92 ]. In line with this result, surface expression of the disialylated ganglioside GD3 suppressed NK-mediated cytotoxicity, while the pharmacological neutralization of GD3 by a specific monoclonal antibody rescued NK-dependent clearance of senescent cells in a mouse model of bleomycin-induced pulmonary fibrosis [ 93 ]. Recent works consistently report that the senescent cells present in the tissues of naturally aged mice and in specimens from idiopathic fibrosis patients displayed heightened expression of the immune checkpoint molecule PD-L1 [ 94 , 95 ].…”

Current state-of-the-art on ganglioside-mediated immune modulation in the tumor microenvironment

“…This is due to a transcriptional upregulation during senescence of the gene encoding the enzyme ST8Sia1, which is responsible for GD3 synthesis. Increased levels of GD3 lead to an immunosuppressive effect on NK cells in vitro and in vivo by binding to Siglec-7 receptor on NK cells [107].…”