Senescence rewires microenvironment sensing to facilitate anti-tumor immunity (scRNA-Seq)

Cellular senescence involves a stable cell cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune competent tumor model in which senescence triggers CD8 T cell-mediated tumor rejection, we show that senescence also remodels cell surface proteome to alter how they sense environmental factors, as exemplified by Type II interferon gamma (IFN-γ). Compared to proliferating cells, senescent cells upregulate IFN-γ receptor, become hypersensitized to microenvironmental IFN-γ, and more robustly induce antigen presenting machinery -effects also recapitulated in human tumor cells treated with senescence-inducing drugs. Disruption of the IFN-γ sensing by senescent cells blunts their immune-mediated clearance without disabling their characteristic secretory program or immune cell recruitment. Our results demonstrate that senescent cells have an enhanced ability to both send and receive environmental signals, and imply that each process is required for their effective immune surveillance. Characterization of single-cell transcriptional profiles of immune cells (CD45+) isolated directly by FACS from p53 off and p53 On (day 8) liver tumor-bearing mice to assess the effects of p53-restoration induced senescence in tumor cells on the immune compartments. 2-3 biological replicates (independent mice) were used per experimental condition.