期刊
JCI INSIGHT
卷 4, 期 14, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.124716
关键词
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资金
- NIH [AG09909, AG017242, CA097186, CA165573, R01CA093678, R01AI113041, R01CA204021]
- SENS Foundation
- US Department of Defense Prostate Cancer Research Program [PC111703]
- Breast Cancer Research Foundation
- Swim Across America Funds
- UCSF Breast Oncology Research and Development Program
- Give Breast Cancer The Boot Program
- Angela and Shu Kai Chan Endowed chair
- Tri-Valley SOCKs program
Cellular senescence is a tumor-suppressive mechanism that can paradoxically contribute to aging pathologies. Despite evidence of immune clearance in mouse models, it is not known how senescent cells (SnCs) persist and accumulate with age or in tumors in individuals. Here, we identify cooperative mechanisms that orchestrate the immunoevasion and persistence of normal and cancer human SnCs through extracellular targeting of natural killer receptor signaling. Damaged SnCs avoided immune recognition through MMP-dependent shedding of NKG2D ligands reinforced via paracrine suppression of NKG2D receptor-mediated immunosurveillance. These coordinated immunoediting processes were evident in residual, drug-resistant tumors from cohorts of more than 700 prostate and breast cancer patients treated with senescence-inducing genotoxic chemotherapies. Unlike in mice, these reversible senescence subversion mechanisms were independent of p53/p16 and exacerbated in oncogenic RAS-induced senescence. Critically, the p16(INK4A) tumor suppressor could disengage the senescence growth arrest from the damage-associated immune senescence program, which was manifest in benign nevus lesions, where indolent SnCs accumulated over time and preserved a non-proinflammatory tissue microenvironment maintaining NKG2D-mediated immunosurveillance. Our study shows how subpopulations of SnCs elude immunosurveillance and reveals potential secretome-targeted therapeutic strategies to selectively eliminate - and restore the clearance of - the detrimental SnCs that actively persist after chemotherapy and accumulate at sites of aging pathologies.
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