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posted on 2023-04-04, 00:44 authored by Hsuan-An Chen, Yu-Jui Ho, Riccardo Mezzadra, Jose M. Adrover, Ryan Smolkin, Changyu Zhu, Katharina Woess, Nicholas Bernstein, Georgia Schmitt, Linda Fong, Wei Luan, Alexandra Wuest, Sha Tian, Xiang Li, Caroline Broderick, Ronald C. Hendrickson, Mikala Egeblad, Zhenghao Chen, Direna Alonso-Curbelo, Scott W. Lowe Supplementary Video S2 from Senescence Rewires Microenvironment Sensing to Facilitate Antitumor Immunity
Funding
National Cancer Institute (NCI)
United States Department of Health and Human Services
Find out more..."la Caixa" Foundation ("la Caixa")
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)
Cancer Research Institute (CRI)
Cold Spring Harbor Laboratory (CSHL)
Calico Life Sciences grants
Howard Hughes Medical Institute (HHMI)
Institute for Research in Biomedicine (IRB Barcelona)
History
ARTICLE ABSTRACT
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 liver cancer model in which senescence triggers CD8 T cell–mediated tumor rejection, we show that senescence also remodels the cell-surface proteome to alter how tumor cells sense environmental factors, as exemplified by type II interferon (IFNγ). Compared with proliferating cells, senescent cells upregulate the IFNγ receptor, become hypersensitized to microenvironmental IFNγ, and more robustly induce the antigen-presenting machinery—effects also recapitulated in human tumor cells undergoing therapy-induced senescence. Disruption of IFNγ sensing in senescent cells blunts their immune-mediated clearance without disabling the senescence state or its characteristic secretory program. 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.
Our work uncovers an interplay between tissue remodeling and tissue-sensing programs that can be engaged by senescence in advanced cancers to render tumor cells more visible to the adaptive immune system. This new facet of senescence establishes reciprocal heterotypic signaling interactions that can be induced therapeutically to enhance antitumor immunity.See related article by Marin et al., p. 410.This article is highlighted in the In This Issue feature, p. 247
