Telomere Shortening in Peripheral Leukocytes Is Associated With Poor Survival in Cancer Patients Treated With Immune Checkpoint Inhibitor Therapy
Open accessAbstract
Background: Immune checkpoint inhibitor (ICI) therapy represents a new standard of care for an increasing number of malignancies. Nevertheless, response rates and outcome of ICI treatment vary between individuals and the identification of predictive markers or hints towards immune cell exhaustion during therapy has remained a major challenge. Leukocyte telomere length is an established predictive biomarker of replicative aging and cellular proliferative potential in various hematological diseases. However, its relevance in the context of ICI therapy has not been investigated to date. Here, we analyze the age-adapted delta telomere length (ΔTL) of peripheral leukocytes as a potential predictive and prognostic marker in patients undergoing ICI therapy. Methods: Age-adapted delta telomere length (ΔTL) of 84 patients treated with ICIs for solid malignancies was measured via quantitative real-time PCR. ΔTL was correlated with outcome and clinical data. Results: ΔTL was not significantly altered between patients with different tumor entities or tumor stages and did not predict tumor response to ICI therapy. However, ΔTLs at initiation of treatment were a prognostic marker for overall survival (OS). When using a calculated ideal cut-off value, the median OS in patients with shorter ΔTL was 5.7 months compared to 18.0 months in patients showing longer ΔTL. The prognostic role of age-adapted ΔTL was further confirmed by uni- and multivariate Cox-regression analyses. Conclusion: In the present study, we demonstrate that shorter telomere lengths in peripheral blood leukocytes are associated with a significantly impaired outcome in patients receiving ICI therapy across different malignancies. We explain our findings by hypothesizing an older replicative age in peripheral leukocytes of patients with an impaired overall survival, reflected by a premature TL shortening. Whether this association is ICI-specific remains unknown. Further follow-up studies are needed to provide insights about the exact mechanism of how shortened telomeres eventually affect OS and could help guiding therapeutic decisions in future.
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
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?
Improving telomere length and increasing telomerase activity may augment the efficacy of immune-mediated therapies such as ACT and ICIs.
“This observation implies that improving telomere length (TL) and increasing telomerase activity (TA) may augment the efficacy of immune-mediated therapies such as ACT and ICIs [30].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [30]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982 · see citing works
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck
Ferris, R. L., Blumenschein, G., Fayette, J., Guigay, J., Colevas, A. D., Licitra, L., Harrington, K., Kasper, S., Vokes, E. E., Even, C., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1602252 · Cited by 5,101 · see citing works
A guide to cancer immunotherapy: from T cell basic science to clinical practice
Waldman, A. D., Fritz, J. M., & Lenardo, M. J. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0306-5 · Cited by 4,154 · see citing works
Brahmer, J. R., Lacchetti, C., Schneider, B. J., Atkins, M. B., Brassil, K. J., Caterino, J. M., Chau, I., Ernstoff, M. S., Gardner, J. M., Ginex, P., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.77.6385 · Cited by 3,713 · see citing works
The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy
Havel, J. J., Chowell, D., & Chan, T. A. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0116-x · Cited by 2,286 · see citing works
Regulation and Function of the PD-L1 Checkpoint
Sun, C., Mezzadra, R., & Schumacher, T. N. (2018) · Immunity · doi:10.1016/j.immuni.2018.03.014 · Cited by 2,187 · see citing works
The diverse functions of the PD1 inhibitory pathway
Sharpe, A. H., & Pauken, K. E. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.108 · Cited by 1,980 · see citing works
Alsaab, H. O., Sau, S., Alzhrani, R. M., Tatiparti, K., Bhise, K., Kashaw, S. K., & Iyer, A. K. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00561 · Cited by 1,715 · see citing works
Blank, C. U., Haining, W. N., Held, W., Hogan, P. G., Kallies, A., Lugli, E., Lynn, R. C., Philip, M., Rao, A., Restifo, N. P., et al. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0221-9 · Cited by 1,603 · see citing works
Mechanisms of resistance to immune checkpoint inhibitors
Jenkins, R. W., Barbie, D. A., & Flaherty, K. T. (2018) · British Journal of Cancer · doi:10.1038/bjc.2017.434 · Cited by 1,383 · see citing works
Chronic inflammation induces telomere dysfunction and accelerates ageing in mice
Jurk, D., Wilson, C., Passos, J. F., Oakley, F., Correia-Melo, C., Greaves, L., Saretzki, G., Fox, C., Lawless, C., Anderson, R., et al. (2014) · Nature Communications · doi:10.1038/ncomms5172 · Cited by 814 · see citing works
Motzer, R. J., Rini, B. I., McDermott, D. F., Arén Frontera, O., Hammers, H. J., Carducci, M. A., Salman, P., Escudier, B., Beuselinck, B., Amin, A., et al. (2019) · The Lancet Oncology · doi:10.1016/s1470-2045(19)30413-9 · Cited by 775 · see citing works
Telomere length, stem cells and aging
Blasco, M. A. (2007) · Nature Chemical Biology · doi:10.1038/nchembio.2007.38 · Cited by 747 · see citing works
Rufer, N., Brümmendorf, T. H., Kolvraa, S., Bischoff, C., Christensen, K., Wadsworth, L., Schulzer, M., & Lansdorp, P. M. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.2.157 · Cited by 709 · see citing works
Self-citationA clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring
Alpert, A., Pickman, Y., Leipold, M., Rosenberg-Hasson, Y., Ji, X., Gaujoux, R., Rabani, H., Starosvetsky, E., Kveler, K., Schaffert, S., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0381-y · Cited by 513 · see citing works
Immunosenescence: a key player in cancer development
Lian, J., Yue, Y., Yu, W., & Zhang, Y. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00986-z · Cited by 510 · see citing works
Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors
Bai, R., Lv, Z., Xu, D., & Cui, J. (2020) · Biomarker Research · doi:10.1186/s40364-020-00209-0 · Cited by 469 · see citing works
The roles of senescence and telomere shortening in cardiovascular disease
Fyhrquist, F., Saijonmaa, O. J., & Strandberg, T. E. (2013) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2013.30 · Cited by 368 · see citing works
Cigarette smoking and telomere length: A systematic review of 84 studies and meta-analysis
Astuti, Y., Wardhana, A. P., Watkins, J. A., & Wulaningsih, W. (2017) · Environmental Research · doi:10.1016/j.envres.2017.06.038 · Cited by 329 · see citing works
Telomere Length and All-Cause Mortality: A Meta-analysis
Wang, Q., Zhan, Y., Pedersen, N. L., Fang, F., & Hägg, S. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.09.002 · Cited by 322 · see citing works
Koch, A. H., Voigt, S., Kruschinski, C., et al. (2011) · Critical Care · doi:10.1186/cc10037 · Cited by 280 · see citing works
Simple Prognostic Model for Patients With Advanced Cancer Based on Performance Status
Jang, R. W.-J., Caraiscos, V. B., Swami, N., et al. (2014) · Journal of Oncology Practice · doi:10.1200/jop.2014.001457 · Cited by 275 · see citing works
Telomere length in leukocyte subpopulations of patients with aplastic anemia
Brümmendorf, T. H., Maciejewski, J. P., Mak, J., Young, N. S., & Lansdorp, P. M. (2001) · Blood · doi:10.1182/blood.v97.4.895 · Cited by 233 · see citing works
Short Telomere Length, Cancer Survival, and Cancer Risk in 47102 Individuals
Weischer, M., Nordestgaard, B. G., Cawthon, R., Freiberg, J., Tybjærg‐Hansen, A., & Bojesen, S. E. (2013) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djt016 · Cited by 228 · see citing works
Dudnik, E., Peled, N., Nechushtan, H., Wollner, M., Onn, A., Agbarya, A., Moskovitz, M. T., Keren, S., Popovits‐Hadari, N., Urban, D., et al. (2018) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2018.04.024 · Cited by 215 · see citing works
Telomere dysfunction, autoimmunity and aging.
(2011) · Europe PMC (PubMed Central) · Cited by 138 · see citing works
Telomere length measurements in leukocyte subsets by automated multicolor flow‐FISH
Baerlocher, G. M., & Lansdorp, P. M. (2003) · Cytometry Part A · doi:10.1002/cyto.a.10064 · Cited by 112 · see citing works
The Effects of Obesity on Anti-Cancer Immunity and Cancer Immunotherapy
Woodall, M. J., Neumann, S., Campbell, K., Pattison, S. T., & Young, S. L. (2020) · Cancers · doi:10.3390/cancers12051230 · Cited by 105 · see citing works
Reconstructing the in vivo dynamics of hematopoietic stem cells from telomere length distributions
Werner, B., Beier, F., Hummel, S., Balabanov, S., Lassay, L., Orlikowsky, T., Dingli, D., Brümmendorf, T. H., & Traulsen, A. (2015) · eLife · doi:10.7554/elife.08687 · Cited by 95 · see citing works
Self-citationBrümmendorf, T. H., & Balabanov, S. (2006) · Leukemia · doi:10.1038/sj.leu.2404339 · Cited by 94 · see citing works
Self-citationRuitenberg, J. J., Mulder, C. B., Maino, V. C., LANDAY, A. L., & Ghanekar, S. (2006) · BMC Immunology · doi:10.1186/1471-2172-7-11 · Cited by 84 · see citing works
Longitudinal studies of telomere length in feline blood cells
Brümmendorf, T. H., Mak, J., Sabo, K. M., Baerlocher, G. M., Dietz, K., Abkowitz, J. L., & Lansdorp, P. M. (2002) · Experimental Hematology · doi:10.1016/s0301-472x(02)00888-3 · Cited by 78 · see citing works
Self-citationSakaguchi, H., Nishio, N., Hama, A., Kawashima, N., Wang, X., Narita, A., Doisaki, S., Xu, Y., Muramatsu, H., Yoshida, N., et al. (2014) · Haematologica · doi:10.3324/haematol.2013.091165 · Cited by 47 · see citing works
Ferreira, M. S. V., Kirschner, M., Halfmeyer, I., Estrada, N., Xicoy, B., Isfort, S., Vieri, M., Zamora, L., Abels, A., Bouillon, A., et al. (2019) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14248 · Cited by 44 · see citing works
Self-citationPredicting Tumor Response to PD-1 Blockade
Ding, L., & Chen, F. (2019) · New England Journal of Medicine · doi:10.1056/nejmcibr1906340 · Cited by 34 · see citing works
Boeck, C., Salinas-Manrique, J., Calzia, E., Radermacher, P., Arnim, C. A. F. V., Dietrich, D. E., Kolassa, I., & Karabatsiakis, A. (2018) · Scientific Reports · doi:10.1038/s41598-018-26867-7 · Cited by 32 · see citing works
Bouillon, A., Ferreira, M. S. V., Awad, S. A., Richter, J., Hochhaus, A., Kunzmann, V., Dengler, J. B., Janssen, J. J. W. M., Ossenkoppele, G. J., Westerweel, P. E., et al. (2018) · Blood Advances · doi:10.1182/bloodadvances.2018017772 · Cited by 32 · see citing works
Self-citationLoosen, S. H., den Bosch, V. V., Gorgulho, J., et al. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10071361 · Cited by 30 · see citing works
Self-citationVieri, M., Kirschner, M., Tometten, M., Abels, A., Rolles, B., Isfort, S., Panse, J., Brümmendorf, T. H., & Beier, F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197196 · Cited by 30 · see citing works
Self-citationWenn, K., Tomala, L., Wilop, S., Vankann, L., Hasenbank, C., Frank, O., Hochhaus, A., Giles, F. J., Lange, T., Müller, M. C., et al. (2015) · Leukemia · doi:10.1038/leu.2015.245 · Cited by 21 · see citing works
Self-citationLoosen, S. H., Gorgulho, J., Jördens, M. S., Schulze-Hagen, M. F., Beier, F., Vucur, M., Schneider, A. T., Koppe, C., Mertens, A., Kather, J. N., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.646883 · Cited by 16 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- [2]Larkin J Chiarion-Sileni V Gonzalez R Grob J-J Rutkowski P Lao CD. Five-Year Survival With Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med (2019) 381: 1535–46. 10.1056/NEJMoa1910836 31562797 · DOI · Paper page
Cited by
Sorted by citations
Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy
Nikolouzakis, T. K., Chrysos, E., Docea, A. O., Fragkiadaki, P., Souglakos, J., Tsiaoussis, J., & Tsatsakis, A. (2024) · Cancers · doi:10.3390/cancers16111995 · Cited by 37 · see citing works
- Authors
- Rolles, B., Gorgulho, J., Tometten, M., Roderburg, C., Vieri, M., Abels, A., Vucur, M., Heymann, F., Tacke, F., Brümmendorf, T. H., Luedde, T., Beier, F., & Loosen, S. H.
- Affiliations
- RWTH Aachen University (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Düsseldorf University Hospital (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Corresponding author
- Luedde, Tom
- ORCID
- Venue
- Frontiers in Oncology
- Publisher
- Frontiers Media SA
- Published
- 2021-08-19
- Volume
- 11
- Pages
- 729207-729207
- ISSN
- 2234-943X (ISSN-L)
- PMC
- PMC8417059
- OpenAlex
- W3194341994
- Cited by
- 12
- References
- 41
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 2
- FWCI
- 1.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
- RWTH Publications (RWTH Aachen)
- Funders
- H2020 European Research Council
- Deutsche Krebshilfe
- Deutsche Forschungsgemeinschaft
- RWTH Aachen University
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- telomere length, immune checkpoint inhibitors, peripheral blood leukocytes, prognostic factors, overall survival, replicative senescence, immune exhaustion, cancer immunotherapy, predictive biomarkers
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
