p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells.
Journal
Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575
Informations de publication
Date de publication:
05 Aug 2024
05 Aug 2024
Historique:
received:
18
01
2023
accepted:
25
06
2024
medline:
6
8
2024
pubmed:
6
8
2024
entrez:
5
8
2024
Statut:
aheadofprint
Résumé
The accumulation of senescent cells promotes ageing and age-related diseases, but molecular mechanisms that senescent cells use to evade immune clearance and accumulate in tissues remain to be elucidated. Here we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in ageing and chronic inflammation. We show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via downregulation of its ubiquitin-dependent degradation. p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors on effector cells leads to the elimination of PD-L1 and p16-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of targeting PD-L1 to improve immunosurveillance of senescent cells and ameliorate senescence-associated inflammation.
Identifiants
pubmed: 39103548
doi: 10.1038/s41556-024-01465-0
pii: 10.1038/s41556-024-01465-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Israel Science Foundation (ISF)
ID : 2633/17; 1626/20
Informations de copyright
© 2024. The Author(s).
Références
Childs, B. G., Durik, M., Baker, D. J. & van Deursen, J. M. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat. Med. 21, 1424–1435 (2015).
pubmed: 26646499
pmcid: 4748967
doi: 10.1038/nm.4000
Baker, D. J. et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).
pubmed: 26840489
pmcid: 4845101
doi: 10.1038/nature16932
Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).
pubmed: 22048312
pmcid: 3468323
doi: 10.1038/nature10600
Schoenwaelder, S. M. et al. Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets. Blood 118, 1663–1674 (2011).
pubmed: 21673344
doi: 10.1182/blood-2011-04-347849
Pereira, B. I. et al. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8
pubmed: 31160572
doi: 10.1038/s41467-019-10335-5
Karin, O., Agrawal, A., Porat, Z., Krizhanovsky, V. & Alon, U. Senescent cell turnover slows with age providing an explanation for the Gompertz law. Nat. Commun. 10, 5495 (2019).
pubmed: 31792199
pmcid: 6889273
doi: 10.1038/s41467-019-13192-4
Yousefzadeh, M. J. et al. An aged immune system drives senescence and ageing of solid organs. Nature 594, 100–105 (2021).
pubmed: 33981041
pmcid: 8684299
doi: 10.1038/s41586-021-03547-7
Ovadya, Y. et al. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat. Commun. 9, 5435 (2018).
pubmed: 30575733
pmcid: 6303397
doi: 10.1038/s41467-018-07825-3
Yosef, R. et al. p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling. EMBO J. 36, 2280–2295 (2017).
pubmed: 28607003
pmcid: 5538795
doi: 10.15252/embj.201695553
Yosef, R. et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 7, 11190 (2016).
pubmed: 27048913
pmcid: 4823827
doi: 10.1038/ncomms11190
Majewska, J. & Krizhanovsky, V. Breathe it in—spotlight on senescence and regeneration in the lung. Mech. Ageing Dev. 199, 111550 (2021).
pubmed: 34352324
doi: 10.1016/j.mad.2021.111550
Biran, A. et al. Quantitative identification of senescent cells in aging and disease. Aging Cell 16, 661–671 (2017).
pubmed: 28455874
pmcid: 5506427
doi: 10.1111/acel.12592
Prieto, L. I. et al. Senescent alveolar macrophages promote early-stage lung tumorigenesis. Cancer Cell 41, 1261–1275.e6 (2023).
pubmed: 37267954
pmcid: 10524974
doi: 10.1016/j.ccell.2023.05.006
Sagiv, A. et al. p53 in bronchial club cells facilitates chronic lung inflammation by promoting senescence. Cell Rep. 22, 3468–3479 (2018).
pubmed: 29590616
doi: 10.1016/j.celrep.2018.03.009
Barnes, P. J. et al. Chronic obstructive pulmonary disease. Nat. Rev. Dis. Prim. 1, 15076 (2015).
pubmed: 27189863
doi: 10.1038/nrdp.2015.76
Hewitt, R. J. & Lloyd, C. M. Regulation of immune responses by the airway epithelial cell landscape. Nat. Rev. Immunol. 21, 347–362 (2021).
pubmed: 33442032
pmcid: 7804588
doi: 10.1038/s41577-020-00477-9
Carlier, F. M., de Fays, C. & Pilette, C. Epithelial barrier dysfunction in chronic respiratory diseases. Front. Physiol. 12, 691227 (2021).
pubmed: 34248677
pmcid: 8264588
doi: 10.3389/fphys.2021.691227
Rodier, F. et al. DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J. Cell Sci. 124, 68–81 (2011).
pubmed: 21118958
doi: 10.1242/jcs.071340
Asghar, U., Witkiewicz, A. K., Turner, N. C. & Knudsen, E. S. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov. 14, 130–146 (2015).
pubmed: 25633797
pmcid: 4480421
doi: 10.1038/nrd4504
Flick, K. & Kaiser, P. Protein degradation and the stress response. Semin. Cell Dev. Biol. 23, 515–522 (2012).
pubmed: 22414377
pmcid: 3376211
doi: 10.1016/j.semcdb.2012.01.019
Gou, Q. et al. PD-L1 degradation pathway and immunotherapy for cancer. Cell Death Dis. 11, 955 (2020).
pubmed: 33159034
pmcid: 7648632
doi: 10.1038/s41419-020-03140-2
Ang, X. L. & Wade Harper, J. SCF-mediated protein degradation and cell cycle control. Oncogene 24, 2860–2870 (2005).
pubmed: 15838520
doi: 10.1038/sj.onc.1208614
Cha, J. H., Chan, L. C., Li, C. W., Hsu, J. L. & Hung, M. C. Mechanisms controlling PD-L1 expression in cancer. Mol. Cell 76, 359–370 (2019).
pubmed: 31668929
pmcid: 6981282
doi: 10.1016/j.molcel.2019.09.030
Onorati, A. et al. Upregulation of PD-L1 in senescence and aging. Mol. Cell. Biol. 42, e0017122 (2022).
pubmed: 36154662
doi: 10.1128/mcb.00171-22
Zhang, J. et al. Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance. Nature 553, 91–95 (2018).
pubmed: 29160310
doi: 10.1038/nature25015
Sato, F. et al. Prognostic impact of p16 and PD-L1 expression in patients with oropharyngeal squamous cell carcinoma receiving a definitive treatment. J. Clin. Pathol. 72, 542–549 (2019).
pubmed: 31113825
doi: 10.1136/jclinpath-2019-205818
Katzenelenbogen, Y. et al. Coupled scRNA-seq and intracellular protein activity reveal an immunosuppressive role of TREM2 in cancer. Cell 182, 872–885.e19 (2020).
pubmed: 32783915
doi: 10.1016/j.cell.2020.06.032
Coleman, M. M. et al. Alveolar macrophages contribute to respiratory tolerance by inducing FoxP3 expression in naive T cells. Am. J. Respir. Cell Mol. Biol. 48, 773–780 (2013).
pubmed: 23492186
doi: 10.1165/rcmb.2012-0263OC
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
pubmed: 22437870
pmcid: 4856023
doi: 10.1038/nrc3239
Dahan, R. et al. FcγRs modulate the anti-tumor activity of antibodies targeting the PD-1/PD-L1 axis. Cancer Cell 28, 285–295 (2015).
pubmed: 26373277
doi: 10.1016/j.ccell.2015.08.004
Bhat, P., Leggatt, G., Waterhouse, N. & Frazer, I. H. Interferon-γ derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity. Cell Death Dis. 8, e2836 (2017).
pubmed: 28569770
pmcid: 5520949
doi: 10.1038/cddis.2017.67
Wang, T.-W. et al. Blocking PD-L1–PD-1 improves senescence surveillance and ageing phenotypes. Nature 611, 358–364 (2022).
pubmed: 36323784
doi: 10.1038/s41586-022-05388-4
Alpert, A. et al. A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring. Nat. Med. 25, 487–495 (2019).
pubmed: 30842675
pmcid: 6686855
doi: 10.1038/s41591-019-0381-y
Reyes, N. S. et al. Sentinel p16(INK4a+) cells in the basement membrane form a reparative niche in the lung. Science 378, 192–201 (2022).
pubmed: 36227993
pmcid: 10621323
doi: 10.1126/science.abf3326
Sender, R. et al. The total mass, number, and distribution of immune cells in the human body. Proc. Natl Acad. Sci. USA 120, e2308511120 (2023).
pubmed: 37871201
pmcid: 10623016
doi: 10.1073/pnas.2308511120
Lumeng, C. N. et al. Aging is associated with an increase in T cells and inflammatory macrophages in visceral adipose tissue. J. Immunol. 187, 6208–6216 (2011).
pubmed: 22075699
doi: 10.4049/jimmunol.1102188
Hilmer, S. N., Cogger, V. C. & Le Couteur, D. G. Basal activity of Kupffer cells increases with old age. J. Gerontol. A Biol. Sci. Med Sci. 62, 973–978 (2007).
pubmed: 17895435
doi: 10.1093/gerona/62.9.973
Ross, J. B. et al. Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Nature 628, 162–170 (2024).
pubmed: 38538791
doi: 10.1038/s41586-024-07238-x
Zhou, Z. et al. Type 2 cytokine signaling in macrophages protects from cellular senescence and organismal aging. Immunity 57, 513–527.e6 (2024).
pubmed: 38262419
doi: 10.1016/j.immuni.2024.01.001
Wilk, C. M. et al. Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders. Immunity 56, 2790–2802.e6 (2023).
pubmed: 38091952
doi: 10.1016/j.immuni.2023.11.011
Haston, S. et al. Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer. Cancer Cell 41, 1242–1260.e6 (2023).
pubmed: 37267953
doi: 10.1016/j.ccell.2023.05.004
Chen, J., Jiang, C. C., Jin, L. & Zhang, X. D. Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann. Oncol. 27, 409–416 (2016).
pubmed: 26681673
doi: 10.1093/annonc/mdv615
Escors, D. et al. The intracellular signalosome of PD-L1 in cancer cells. Signal Transduct. Target. Ther. 3, 26 (2018).
pubmed: 30275987
pmcid: 6160488
doi: 10.1038/s41392-018-0022-9
Wiederschain, D. et al. Single-vector inducible lentiviral RNAi system for oncology target validation. Cell Cycle 8, 498–504 (2009).
pubmed: 19177017
doi: 10.4161/cc.8.3.7701
Perez-Correa, J. F., Tharmapalan, V., Geiger, H. & Wagner, W. Epigenetic clocks for mice based on age-associated regions that are conserved between mouse strains and human. Front. Cell Dev. Biol. 10, 902857 (2022).
pubmed: 35721486
pmcid: 9204067
doi: 10.3389/fcell.2022.902857
Jaitin, D. A. et al. Massively parallel single-cell RNA-seq for marker-free decomposition of tissues into cell types. Science 343, 776–779 (2014).
pubmed: 24531970
pmcid: 4412462
doi: 10.1126/science.1247651
Kohen, R. et al. UTAP: User-friendly Transcriptome Analysis Pipeline. BMC Bioinf. 20, 154 (2019).
doi: 10.1186/s12859-019-2728-2
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
pubmed: 25516281
pmcid: 4302049
doi: 10.1186/s13059-014-0550-8
Korotkevich, G. et al. Fast gene set enrichment analysis. Preprint at bioRxiv https://doi.org/10.1101/060012 (2021).
Liberzon, A. et al. Molecular signatures database (MSigDB) 3.0. Bioinformatics 27, 1739–1740 (2011).
pubmed: 21546393
pmcid: 3106198
doi: 10.1093/bioinformatics/btr260