Synapse - Senescence rewires microenvironment sensing to facilitate antitumor immunity

Senescence rewires microenvironment sensing to facilitate antitumor immunity Journal Article

Authors:	Chen, H. A.; Ho, Y. J.; Mezzadra, R.; Adrover, J. M.; Smolkin, R.; Zhu, C.; Woess, K.; Bernstein, N.; Schmitt, G.; Fong, L.; Luan, W.; Wuest, A.; Tian, S.; Li, X.; Broderick, C.; Hendrickson, R. C.; Egeblad, M.; Chen, Z.; Alonso-Curbelo, D.; Lowe, S. W.
Article Title:	Senescence rewires microenvironment sensing to facilitate antitumor immunity
Abstract:	Cellular senescence involves a stable cell-cycle arrest coupled to a secretory pro-gram 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 exemplifi ed by type II interferon (IFN gamma). Compared with proliferat-ing cells, senescent cells upregulate the IFN gamma receptor, become hypersensitized to microenvironmental IFN gamma , and more robustly induce the antigen-presenting machinery-effects also recapitulated in human tumor cells undergoing therapy-induced senescence. Disruption of IFN gamma 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.SIGNIFICANCE: Our work uncovers an interplay between tissue remodeling and tissue-sensing pro-grams 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.
Keywords:	dynamics; therapy; p53; resistance; ifn-gamma; mechanisms; tumor-cells; rna-seq; cellular senescence; secretory phenotype
Journal Title:	Cancer Discovery
Volume:	13
Issue:	2
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2023-02-01
Start Page:	432
End Page:	453
Language:	English
ACCESSION:	WOS:000928460200001
DOI:	10.1158/2159-8290.Cd-22-0528
PROVIDER:	wos
PMCID:	PMC9901536
PUBMED:	36302222
Notes:	Article -- Source: Wos