Predictive and prognostic value of LPS-stimulated cytokine secretion in metastatic non-small cell lung cancer

Abstract

Objective

Cancer patients usually develop malnutrition which may alter their innate immune system integrity. The aim of this study was to investigate the clinical relevance of chemokine response after lipopolysaccharide (LPS)-stimulation in metastatic non-small cell lung cancer (NSCLC).

Methods

Blood samples from metastatic NSCLC patients were incubated with LPS before the onset of systemic therapy. Interleukin (IL)-6 and IL-8 levels at baseline and after LPS-stimulation were measured and the fold change compared to baseline levels was evaluated as the stimulation index for each cytokine per patient. Results were correlated with sex, age, smoking status, histologic subtype, performance status (PS), albumin, Mini Nutritional Assessment (MNA) status and clinical outcomes.

Results

Totally 103 patients were evaluated. Mean (±SD) stimulation index was 37.6 (±57.8) for IL-6 and 76.7 (±133.4) for IL-8. The disease control rate after first-line chemotherapy was 44/80 (55 %) and the mean (±SD) progression-free survival (PFS) and overall survival (OS) were 4.2 (±3.9) and 9.2 (±1.1) months, respectively. MNA, PS, albumin, IL-6 and IL-8 stimulation indices were univariately associated with PFS and OS. IL-8 stimulation index emerged as an independent predictor of both PFS and OS, along with PS, and albumin levels.

Conclusion

The extent of IL-6 and IL-8 stimulation after ex vivo induction with LPS is an important predictor of clinical outcome in metastatic NSCLC patients.

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References

  1. 1.

    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.

    PubMed  Article  Google Scholar 

  2. 2.

    Mantovani A, Allavena P, Sica A. Tumour-associated macrophages as a prototypic type II polarised phagocyte population: role in tumour progression. Eur J Cancer. 2004;40:1660–7.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Korkaya H, Liu S, Wicha MS. Regulation of cancer stem cells by cytokine networks: attacking cancer’s inflammatory roots. Clin Cancer Res. 2011;17:6125–9.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996;17:138–46.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Tisdale MJ. Cancer cachexia. Curr Opin Gastroenterol. 2010;26:146–51.

    PubMed  Article  Google Scholar 

  6. 6.

    Wang J, Huang M, Lee P, Komanduri K, Sharma S, Chen G, et al. Interleukin-8 inhibits non-small cell lung cancer proliferation: a possible role for regulation of tumor growth by autocrine and paracrine pathways. J Interferon Cytokine Res. 1996;16:53–60.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Pine SR, Mechanic LE, Enewold L, Chaturvedi AK, Katki HA, Zheng YL, et al. Increased levels of circulating interleukin 6, interleukin 8, C-reactive protein, and risk of lung cancer. J Natl Cancer Inst. 2011;103:1112–22.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Gioulbasanis I, Patrikidou A, Kitikidou K, Papadimitriou K, Vlachostergios PJ, Tsatsanis C, et al. Baseline plasma levels of interleukin-8 in stage IV non-small-cell lung cancer patients: relationship with nutritional status and prognosis. Nutr Cancer. 2012;64:41–7.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Fortunati N, Manti R, Birocco N, Pugliese M, Brignardello E, Ciuffreda L, et al. Pro-inflammatory cytokines and oxidative stress/antioxidant parameters characterize the bio-humoral profile of early cachexia in lung cancer patients. Oncol Rep. 2007;18:1521–7.

    PubMed  CAS  Google Scholar 

  10. 10.

    Yannelli JR, Tucker JA, Hidalgo G, Perkins S, Kryscio R, Hirschowitz EA. Characteristics of PBMC obtained from leukapheresis products and tumor biopsies of patients with non-small cell lung cancer. Oncol Rep. 2009;22:1459–71.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Dahlke E, Schlag R, Langenmayer I, Frankenberger M, Käfferlein E, Subkowski T, et al. Decreased production of TNF and IL-6 in whole blood of CLL patients. Am J Hematol. 1995;49:76–82.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Suzuki K, Koyama T, Kobayashi S, Kobayashi K, Inagaki K, Abe Y, et al. Novel method for detection of ex vivo tumor necrosis factor alpha production by monocytes. J Clin Lab Anal. 2002;16:273–8.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Berthier F, Lambert C, Genin C, Bienvenu J. Evaluation of an automated immunoassay method for cytokine measurement using the Immulite 400 Immunoassay system. Clin Chem Lab Med. 1999;37:593–9.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Vellas B, Guigoz Y, Garry PJ, Nourhashemi F, Bennahum D, Lauque S, et al. The Mini Nutritional Assessment (MNA) and its use in grading the nutritional state of elderly patients. Nutrition. 1999;15:116–22.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Gioulbasanis I, Georgoulias P, Vlachostergios PJ, Baracos V, Ghosh S, Giannousi Z, et al. Mini Nutritional Assessment (MNA) and biochemical markers of cachexia in metastatic lung cancer patients: interrelations and associations with prognosis. Lung Cancer. 2011;74:516–20.

    PubMed  Article  Google Scholar 

  16. 16.

    Enewold L, Mechanic LE, Bowman ED, Zheng YL, Yu Z, Trivers G, et al. Serum concentrations of cytokines and lung cancer survival in African Americans and Caucasians. Cancer Epidemiol Biomarkers Prev. 2009;18:215–22.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Su C, Zhou C, Zhou S, Xu J. Serum cytokine levels in patients with advanced non-small cell lung cancer: correlation with treatment response and survival. Med Oncol. 2011;28:1453–7.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Asselin-Paturel C, Echchakir H, Carayol G, Gay F, Opolon P, Grunenwald D, et al. Quantitative analysis of Th1, Th2 and TGF-beta1 cytokine expression in tumor, TIL and PBL of non-small cell lung cancer patients. Int J Cancer. 1998;77:7–12.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Wei H, Sun R, Xiao W, Feng J, Zhen C, Xu X, et al. Type two cytokines predominance of human lung cancer and its reverse by traditional Chinese medicine TTMP. Cell Mol Immunol. 2004;1:63–70.

    PubMed  CAS  Google Scholar 

  20. 20.

    Trejo YG, Bordenave RH, Beviacqua M, Zanoni L, Rumi LS. Tumor necrosis factor-alfa production by monocytes from lung and colorectal cancer patients. J Exp Clin Cancer Res. 2001;20:71–3.

    PubMed  CAS  Google Scholar 

  21. 21.

    Trejo YG, Bordenave RH, Beviacqua M, Rumi LS. In vitro secretion of cytokines and prostaglandin-E2 by monocytes from lung cancer patients. Respir Med. 2001;95:243–5.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Miotto D, Boschetto P, Bononi I, Milani G, Legorini C, Cavallesco G, et al. CC ligand 2 levels are increased in LPS-stimulated peripheral monocytes of patients with non-small cell lung cancer. Respir Med. 2007;101:1738–43.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Romagnani S. Type 1 T helper and type 2 T helper cells: functions, regulation and role in protection and disease. Int J Clin Lab Res. 1991;21:152–8.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000;25:187–91.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Parry SL, Sebbag M, Feldmann M, Brennan FM. Contact with T cells modulates monocyte IL-10 production: role of T cell membrane TNF-alpha. J Immunol. 1997;158:3673–81.

    PubMed  CAS  Google Scholar 

  26. 26.

    Kallio R, Surcel HM, Syrjälä H. Peripheral mononuclear cell IL-10 and IL-12 production is not impaired in patients with advanced cancer and severe infection. Cytokine. 2002;20:210–4.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Grandel U, Heygster D, Sibelius U, Fink L, Sigel S, Seeger W, et al. Amplification of lipopolysaccharide-induced cytokine synthesis in non-small cell lung cancer/neutrophil cocultures. Mol Cancer Res. 2009;7:1729–35.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Zhao L, Wang L, Ji W, Wang X, Zhu X, Hayman JA, et al. Elevation of plasma TGF-beta1 during radiation therapy predicts radiation-induced lung toxicity in patients with non-small-cell lung cancer: a combined analysis from Beijing and Michigan. Int J Radiat Oncol Biol Phys. 2009;74:1385–90.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Lu H, Zhu S, Qian L, Xiang D, Zhang W, Nie A, et al. Activated expression of the chemokine Mig after chemotherapy contributes to chemotherapy-induced bone marrow suppression and lethal toxicity. Blood. 2012;119:4868–77.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Hirota K, Oishi Y, Taniguchi H, Sawachi K, Inagawa H, Kohchi C, et al. Antitumor effect of inhalatory lipopolysaccharide and synergetic effect in combination with cyclophosphamide. Anticancer Res. 2010;30:3129–34.

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was partly supported by an unrestricted research grant from the Cretan Association for Biomedical Research (CABR).

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Correspondence to P. J. Vlachostergios.

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Vlachostergios, P.J., Gioulbasanis, I., Ghosh, S. et al. Predictive and prognostic value of LPS-stimulated cytokine secretion in metastatic non-small cell lung cancer. Clin Transl Oncol 15, 903–909 (2013). https://doi.org/10.1007/s12094-013-1021-5

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Keywords

  • LPS
  • IL-6
  • IL-8
  • Lung cancer
  • Hospitalization
  • Prognosis