The DOI matches its Crossref record; 91 of the 92 references it cites were found in a registry or an index.
Targetable mechanisms driving immunoevasion of persistent senescent cells link chemotherapy-resistant cancer to aging
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“At younger ages, senescent cells are cleared by the host immune system [63–66]”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [63]
Experimental — accuracy not yet measuredIn the citing paper
“Senescence is also an important mechanism of efficacy in the treatment of breast cancer with PARP inhibitors [59] and many typical chemotherapy agents used to treat breast cancer, such as epirubicin and cyclophosphamide [60].”
From Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies (2020) · cites this paper as [60]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9363 · Cited by 7,477
Cancer immunoediting: from immunosurveillance to tumor escape
Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J., & Schreiber, R. D. (2002) · Nature Immunology · doi:10.1038/ni1102-991 · Cited by 5,393
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011) · Nature · doi:10.1038/nature10600 · Cited by 3,670
Aging, Cellular Senescence, and Cancer
Campisi, J. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183653 · Cited by 2,954 · cited 5×
“relevant in adult organisms, where retaining arrested yet functional cells may help maintain tissue homeostasis (1, 3, 63, 64).”
InfluentialSelf-citationNaturally occurring p16Ink4a-positive cells shorten healthy lifespan
Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., A. Saltness, R., Jeganathan, K. B., Verzosa, G. C., Pezeshki, A., et al. (2016) · Nature · doi:10.1038/nature16932 · Cited by 2,876
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473
Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion
Rodier, F., Coppé, J.-P., Patil, C. K., Hoeijmakers, W. A. M., Muñoz, D. P., Raza, S. R., Freund, A., Campeau, E., Davalos, A. R., & Campisi, J. (2009) · Nature Cell Biology · doi:10.1038/ncb1909 · Cited by 2,232
Self-citationBRAFE600-associated senescence-like cell cycle arrest of human naevi
Michaloglou, C., Vredeveld, L. C. W., Soengas, M. S., Denoyelle, C., Kuilman, T., van der Horst, C. M. A. M., Majoor, D. M., Shay, J. W., Mooi, W. J., & Peeper, D. S. (2005) · Nature · doi:10.1038/nature03890 · Cited by 2,160
The Tumour Microenvironment after Radiotherapy: Mechanisms of Resistance and Recurrence
Barker, H. E., Paget, J. T. E., Khan, A. A., & Harrington, K. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3958 · Cited by 2,144
An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA
Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., Laberge, R.-M., Vijg, J., Van Steeg, H., Dollé, M. E. T., et al. (2014) · Developmental Cell · doi:10.1016/j.devcel.2014.11.012 · Cited by 2,045
Self-citation
Research works printed but not linked: 1
- 10.1016/j.cell.2008.06.049 · DOI · Paper page
Cited by
Sorted by citations
Exploiting senescence for the treatment of cancer
Wang, L., Lankhorst, L., & Bernards, R. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-022-00450-9 · Cited by 867
Role of immune cells in the removal of deleterious senescent cells
Kale, A., Sharma, A., Stolzing, A., Desprez, P.-Y., & Campisi, J. (2020) · Immunity & Ageing · doi:10.1186/s12979-020-00187-9 · Cited by 351
Self-citationInterconnections between Inflammageing and Immunosenescence during Ageing
Teissier, T., Boulanger, É., & Cox, L. S. (2022) · Cells · doi:10.3390/cells11030359 · Cited by 323
Mechanisms driving the immunoregulatory function of cancer cells
van Weverwijk, A., & de Visser, K. E. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-022-00544-4 · Cited by 288
Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies
Wyld, L., Bellantuono, I., Tchkonia, T., Morgan, J., Turner, O., Foss, F., George, J., Danson, S., & Kirkland, J. L. (2020) · Cancers · doi:10.3390/cancers12082134 · Cited by 235
“Senescence is also an important mechanism of efficacy in the treatment of breast cancer with PARP inhibitors [59] and many typical chemotherapy agents used to treat breast cancer, such as epirubicin and cyclophosphamide [60].”
Background
Metadata
- Authors
- Muñoz, D. P., Yannone, S. M., Daemen, A., Sun, Y., Vakar-Lopez, F., Kawahara, M., Freund, A. M., Rodier, F., Wu, J. D., Desprez, P.-Y., Raulet, D. H., Nelson, P. S., van ’t Veer, L. J., Campisi, J., & Coppé, J.-P.
- Affiliations
- University of California, San Francisco (US)
- Lawrence Berkeley National Laboratory (US)
- Fred Hutch Cancer Center (US)
- Department of Pathology, University of Washington, Seattle, Washington, USA.
- Buck Institute for Research on Aging (US)
- Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, California, USA.
- University of Washington (US)
- University of California, Berkeley (US)
- Helen Diller Family Comprehensive Cancer Center, Department of Laboratory Medicine, UCSF, San Francisco, California, USA.
- Corresponding author
- Coppé, Jean-Philippe
- ORCID
- Venue
- JCI Insight
- Published
- 2019-07-25
- Volume
- 4
- Issue
- 14
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC6675550
- OpenAlex
- W2952749575
- Cited by
- 162
- References
- 92
- Citations by year
- 2026: 18 · 2025: 18 · 2024: 25 · 2023: 21 · 2022: 30 · 2021: 26 · 2020: 23 · 2019: 1
- FWCI
- 13.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Aging (R56AG009909, R37AG009909, P01AG017242)
- National Cancer Institute (R01CA093678, R01CA204021, R01CA165573, P50CA097186)
- National Institute of Allergy and Infectious Diseases (R01AI113041)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cellular senescence, senescent cells, immune evasion, NKG2D, natural killer cells, matrix metalloproteinases, immune surveillance, immunoediting, chemoresistance, aging, prostate cancer, breast cancer, Ras-induced senescence, p16INK4a, benign nevi, tumor microenvironment
- MeSH terms
- Aging, Animals, Antineoplastic Agents, Biopsy, Breast, Breast Neoplasms, DNA Damage, Female, Humans, Immunologic Surveillance, Male, Metalloendopeptidases, Prostate, Prostatic Neoplasms, Gene Expression Regulation, Neoplastic, Cellular Senescence, Drug Resistance, Neoplasm, Tumor Escape, Cyclin-Dependent Kinase Inhibitor p16, Gene Expression Profiling, Cell Line, Tumor, Tissue Array Analysis, Mice, NK Cell Lectin-Like Receptor Subfamily K, Tumor Microenvironment, Datasets as Topic
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
