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

JCI Insight. 2019 Jun 11;5(14):e124716. doi: 10.1172/jci.insight.124716.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / immunology*
  • Aging / pathology
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Biopsy
  • Breast / pathology
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cellular Senescence / immunology*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA Damage / drug effects
  • Datasets as Topic
  • Drug Resistance, Neoplasm / immunology*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / immunology
  • Humans
  • Immunologic Surveillance / drug effects
  • Immunologic Surveillance / immunology
  • Male
  • Metalloendopeptidases / metabolism
  • Mice
  • NK Cell Lectin-Like Receptor Subfamily K / antagonists & inhibitors
  • NK Cell Lectin-Like Receptor Subfamily K / immunology
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism
  • Prostate / pathology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / pathology
  • Tissue Array Analysis
  • Tumor Escape / drug effects
  • Tumor Escape / immunology*
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology


  • Antineoplastic Agents
  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • KLRK1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily K
  • Metalloendopeptidases