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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.
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“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]
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]
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Desmedt, C., Giobbie‐Hurder, A., Neven, P., Paridaens, R., Christiaens, M., Smeets, A., Lallemand, F., Haibe‐Kains, B., Viale, G., Gelber, R. D., et al. (2009) · BMC Medical Genomics · doi:10.1186/1755-8794-2-40 · Cited by 81
Čížková, M., Cizeron-Clairac, G., Vacher, S., Susini, A., Andrieu, C., Lidereau, R., & Bièche, I. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015647 · Cited by 74
Irradiation induces glioblastoma cell senescence and senescence-associated secretory phenotype
Jeon, H.-Y., Kim, J.-K., Ham, S. W., Oh, S.-Y., Kim, J., Park, J.-B., Lee, J.-Y., Kim, S.-C., & Kim, H. (2016) · Tumor Biology · doi:10.1007/s13277-015-4439-2 · Cited by 73
Senescence as an Amyloid Cascade: The Amyloid Senescence Hypothesis
Walton, C. C., Begelman, D. V., Nguyen, W., & Andersen, J. K. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00129 · Cited by 62
NKG2D Ligand Shedding in Response to Stress: Role of ADAM10
Zingoni, A., Vulpis, E., Loconte, L., & Santoni, A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00447 · Cited by 59
Klöß, S., Chambron, N., Gardlowski, T., Arseniev, L., Koch, J., Esser, R., Glienke, W., Seitz, O., & Koehl, U. (2015) · OncoImmunology · doi:10.1080/2162402x.2015.1055993 · Cited by 50
Raju, S., Kretzmer, L. Z., Koues, O. I., Payton, J. E., Oltz, E. M., Cashen, A. F., Polić, B., Schreiber, R. D., Shaw, A. S., & Markiewicz, M. A. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501982 · Cited by 24
Jun, J.-I., & Lau, L. F. (2010) · Nature Cell Biology · doi:10.1038/ncb1210-1249 · Cited by 17
NKG2D ligands mediate immunosurveillance of senescent cells. Aging-US
Sagiv, A., Burton, D., Moshayev, Z., Wensveen, F. M., Ben‐Dor, S., Golani, O., Polić, B., & Krizhanovsky, V. (2016) · Aging-us · Cited by 8
Flagged first, then by citations
1 of the 92 references couldn’t be matched to a known paper.
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.
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