Format

Send to

Choose Destination
JCI Insight. 2019 Jun 11;5. pii: 124716. doi: 10.1172/jci.insight.124716.

Targetable mechanisms driving immunoevasion of persistent senescent cells link chemotherapy-resistant cancer to aging.

Author information

1
Swim Across America National Laboratory, Children's Hospital Oakland Research Institute, UCSF Benioff Children's Hospital Oakland, Oakland, California, USA.
2
Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, California, USA.
3
Helen Diller Family Comprehensive Cancer Center, Department of Laboratory Medicine, UCSF, San Francisco, California, USA.
4
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
5
Department of Pathology, University of Washington, Seattle, Washington, USA.
6
Buck Institute for Research on Aging, Novato, California, USA.
7
Research Institute, California Pacific Medical Center, San Francisco, California, USA.
8
Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, Berkeley, California, USA.

Abstract

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 avoid immune recognition through MMPs-dependent shedding of NKG2D-ligands reinforced via paracrine suppression of NKG2D receptor-mediated immunosurveillance. These coordinated immunoediting processes are evident in residual, drug-resistant tumors from cohorts of >700 prostate and breast cancer patients treated with senescence-inducing genotoxic chemotherapies. Unlike in mice, these reversible senescence-subversion mechanisms are independent of p53/p16 and exacerbated in oncogenic RAS-induced senescence. Critically, the p16INK4A tumor suppressor can disengage the senescence growth arrest from the damage-associated immune senescence program, which is manifest in benign nevi lesions where indolent SnCs accumulate over time and preserve a non-pro-inflammatory tissue microenvironment maintaining NKG2D-mediated immunosurveillance. Our study shows how subpopulations of SnCs elude immunosurveillance, and reveals 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.

KEYWORDS:

Aging; Cellular senescence; Oncology; Proteases; Tumor suppressors

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation Icon for PubMed Central
Loading ...
Support Center