- A Novel Prognostic Signature Combining Serum Inflammatory Cytokines and Cell-Free Telomere Length in Small Cell Lung Cancer

serum levels of IL-6, IL-8, TNF-α, CRP, and cell-free telomere length (cfTL)

  • Mark Pan 1College of Basic Medical Science, China Three Gorges University, Yichang, Hubei, 443002, China
  • JingYun Fu 1College of Basic Medical Science, China Three Gorges University, Yichang, Hubei, 443002, China
  • Tao Chen 2College of Medicine and Health Science, China Three Gorges University, Yichang, Hubei, 443002, China
DOI: https://doi.org/10.5937/jomb0-63260
Keywords: Small cell lung cancer, inflammation, telomere, senescence, biomarkers, prognosis

Abstract


Background: Small Cell Lung Cancer (SCLC) remains a lethal malignancy with limited prognostic biomarkers. While systemic inflammation contributes to SCLC progression, the integration of cellular senescence biomarkers with inflammatory markers has not been explored. We hypothesized that combining serum inflammatory cytokines with cell-free telomere length would create a superior prognostic tool.

Methods: In this prospective cohort study, 187 extensive-stage SCLC patients were enrolled before first-line chemo-immunotherapy. Baseline serum levels of IL-6, IL-8, TNF-α, CRP, and cell-free telomere length (cfTL) were measured. An Inflamm-Aging Index (IAI) was developed using Cox regression. Primary outcome was overall survival (OS).

Results: High IL-6 (HR 2.14, 95% CI 1.45-3.16, p<0.001) and short cfTL (HR 2.87, 95% CI 1.92-4.29, p<0.001) independently predicted worse OS. The composite IAI stratified patients into low, intermediate, and high-risk groups with median OS of 14.2, 9.1, and 5.3 months, respectively (p<0.0001). The IAI remained independently prognostic after multivariable adjustment (HR 3.42, 95% CI 2.18-5.37, p<0.001). The IAI demonstrated superior discriminative ability (C-index 0.78) compared to individual biomarkers.

Conclusion: The Inflamm-Aging Index, integrating inflammatory cytokines with cellular senescence biomarkers, provides a novel, non-invasive prognostic tool that significantly improves risk stratification in SCLC, potentially guiding personalized therapeutic approaches.

References

1. Rudin CM, Brambilla E, Faivre-Finn C, et al. Small-cell lung cancer. Nat Rev Dis Primers. 2021;7(1):3.
2. Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-9.
3. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-39.
4. Diakos CI, Charles KA, McMillan DC, et al. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 2014;15(11):e493-503.
5. Mantovani A, Allavena P, Sica A, et al. Cancer-related inflammation. Nature. 2008;454(7203):436-44.
6. Hong S, Zheng DW, Zhang C, et al. Pretreatment serum interleukin-6 predicts therapeutic response and survival in small cell lung cancer. Lung Cancer. 2019;138:71-8.
7. Li X, Xing YF, Lei AH, et al. NLRP3 inflammasome: a novel biomarker and therapeutic target in small cell lung cancer. J Thorac Oncol. 2021;16(6):973-85.
8. Kumari N, Dwarakanath BS, Das A, et al. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biol. 2016;37(9):11553-72.
9. Allin KH, Nordestgaard BG. Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer. Crit Rev Clin Lab Sci. 2011;48(4):155-70.
10. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685-705.
11. López-Otín C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell. 2013;153(6):1194-217.
12. Blackburn EH, Epel ES, Lin J. Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science. 2015;350(6265):1193-8.
13. Laprovitera N, Riefolo M, Porcellini E, et al. Cancer-associated telomere alterations: Biomarkers and therapeutic targets. Cancers (Basel). 2021;13(8):1903.
14. Lin J, Cheon J, Brown R, et al. Systematic and cell type-specific telomere length changes in subsets of lymphocytes. J Immunol Res. 2016;2016:5371050.
15. McNally EJ, Luncsford PJ, Armanios M. Long telomeres and cancer risk: the price of cellular immortality. J Clin Invest. 2019;129(9):3474-81.
16. De Vitis M, Berardinelli F, Sgura A. Telomere length maintenance in cancer: at the crossroad between telomerase and alternative lengthening of telomeres (ALT). Int J Mol Sci. 2018;19(2):606.
17. Franceschi C, Garagnani P, Parini P, et al. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576-90.
18. Xia S, Zhang X, Zheng S, et al. An update on inflamm-aging: mechanisms, prevention, and treatment. J Immunol Res. 2016;2016:8426874.
19. Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018;15(9):505-22.
20. Wang WJ, Cai GY, Chen XM. Cellular senescence, senescence-associated secretory phenotype, and chronic kidney disease. Oncotarget. 2017;8(38):64520-33.
21. Micke P, Faldum A, Metz T, et al. Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer--what limits limited disease? Lung Cancer. 2002;37(3):271-6.
22. Elshal MF, McCoy JP. Multiplex bead array assays: performance evaluation and comparison of sensitivity to ELISA. Methods. 2006;38(4):317-23.
23. Norton SE, Lechner JM, Williams T, et al. A stabilizing reagent prevents cell-free DNA contamination by cellular DNA in plasma during blood sample storage and shipping as determined by digital PCR. Clin Biochem. 2013;46(15):1561-5.
24. Cawthon RM. Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic Acids Res. 2009;37(3):e21.
25. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47.
26. Lausen B, Schumacher M. Maximally selected rank statistics. Biometrics. 1992;48(1):73-85.
27. Cox DR. Regression models and life-tables. J R Stat Soc Series B Stat Methodol. 1972;34(2):187-220.
28. Heagerty PJ, Lumley T, Pepe MS. Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics. 2000;56(2):337-44.
29. Harrell FE Jr, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15(4):361-87.
30. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883-99.
31. Johnson DE, O'Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15(4):234-48.
32. McMillan DC. The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients with cancer. Cancer Treat Rev. 2013;39(5):534-40.
33. De Vitis M, Berardinelli F, Sgura A. Telomere length maintenance in cancer: at the crossroad between telomerase and alternative lengthening of telomeres (ALT). Int J Mol Sci. 2018;19(2):606.
34. Rajaraman P, Hauptmann M, Bouffler S, et al. Human individual radiation sensitivity and prospects for prediction. Ann ICRP. 2018;47(3-4):126-41.
35. Lin J, Smith DL, Esteves K, et al. Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic Acids Res. 2019;47(11):e66.
36. Victorelli S, Passos JF. Telomeres and cell senescence - size matters not. EBioMedicine. 2017;21:14-20.
37. Franceschi C, Bonafè M, Valensin S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244-54.
38. von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 2002;27(7):339-44.
39. Coppé JP, Desprez PY, Krtolica A, et al. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118.
40. Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020;288(5):518-36.
Published
2026/06/08
Issue
Ahead of print
Section
Original paper

Copyright (c) 2026 Mark Pan, JingYun Fu, Tao Chen

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