Cellular senescence and adaptive immune responses

Abstract

[eng] Cellular senescence is a response to stress and damage, ant it is known to activate innate immune cells. However, the mechanisms by which senescent cells interact with the adaptive arm of the immune system and their potential ability to trigger adaptive immune responses remain largely unexplored. In this doctoral work, we report that senescent cells combine several characteristics that render them highly immunogenic and thus very efficient in promoting the activation of adaptive immune responses driven by antigen-presenting cells (APCs) and antigen-specific CD8 T cells. These properties include the release of alarmin molecules that can recruit and activate APCs; enhanced delivery of antigens to APCs; activation of interferon signaling; upregulated MHC class I (MHC-I) antigen processing and presentation; and an altered MHC- I immunopeptidome that includes senescence-associated self-peptides, some of which are recognized by specific CD8 T cells. In the context of cancer, the immunization of murine models with viable senescent cancer cells elicits strong anti-tumor protection mediated by adaptive immunity, specifically APCs and CD8 T cells. Interestingly, the anti-tumor protection promoted by senescent cells is superior to that of immunization with dying senescent cells or with those cancer cells undergoing immunogenic cell death. The latter being the gold standard method to boost the immunogenicity of cancer cells and elicit anti-tumor immune protection in both cancer therapy and whole-cell vaccination approaches. Finally, the induction of senescence in patient-derived primary cancer cells also enhances their ability to activate autologous antigen-specific CD8 tumor-infiltrating lymphocytes (TILs), with no effect on autologous non-tumor-reactive TILs. We conclude that senescent cells are provided with combined adjuvanticity and antigenicity that can strongly activate adaptive immunity. In this regard, we propose that the properties of senescent cancer cells can be harnessed to trigger efficient and protective CD8- dependent anti-tumor immune responses.