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The prognostic time dependence of intra-tumoural IFNγ mRNA and protein in patients with breast cancer followed for 14 years after surgery and radiotherapy, without subsequent systemic therapy

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Abstract

There is increasing evidence for the importance of immunity in breast cancer. IFNγ is expected to have a prognostic value based on its major role in innate and specific cell-mediated immunity. In this retrospective study, based on the 14-year follow-up of 73 patients with breast cancer after surgery and radiotherapy but no subsequent systemic therapy, we investigated the prognostic time dependence of intra-tumoural IFNγ mRNA and protein levels. Over the entire 14 years of follow-up, neither IFNγ mRNA nor protein was significantly associated with metastasis outcome by AUC and Cox regression criteria. However, evaluation of the shorter periods has revealed a prognostic significance in the late follow-up period of 7-14 years for IFNγ mRNA and protein with the maximal respective AUCs of 0.72 and 0.73 and hazard ratios of 6.1 and 5.2, respectively. Interestingly, the opposite prognostic association was discovered for IFNγ mRNA and protein in the first 7 years of follow-up, possibly due to the negative correlation of IFNγ protein and mRNA. Moreover, the prognostic association of IFNγ mRNA has shifted from marking the favourable outcome in the first 7 years to poor outcome thereafter. This study contributes to clarification of the previously inconsistent prognostic performance of IFNγ by providing the first prognostic evaluation with long follow-up, time-dependence assessment and absence of any chemotherapy influence.

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Abbreviations

AUC:

area under the receiver operating characteristic (ROC) curve

ER:

oestrogen receptor

PR:

progesterone receptor

pT:

pathological tumour size

References

  1. Annunziato F, Romagnani C, Romagnani S. The 3 major types of innate and adaptive cell-mediated effector immunity. J Allergy Clin Immunol 2015; 135: 626.

    Article  PubMed  CAS  Google Scholar 

  2. Gough DJ, Levy DE, Johnstone RW, Clarke CJ. IFNgamma signaling-does it mean JAK-STAT? Cytokine Growth Factor Rev 2008; 19: 383.

    Article  PubMed  CAS  Google Scholar 

  3. Zaidi MR, Merlino G. The two faces of interferon-gamma in cancer. Clin Cancer Res 2011; 17: 6118.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nature Rev Immunol 2006; 6: 836.

    Article  CAS  Google Scholar 

  5. Zhang X, Zeng Y, Qu Q, et al. PD-L1 induced by IFN-gamma from tumour-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer. Int J Clin Oncol 2017; 6: 1026.

    Article  CAS  Google Scholar 

  6. Parker BS, Rautela J, Hertzog PJ. Antitumour actions of interferons: implications for cancer therapy. Nat Rev Cancer 2016; 16: 131.

    Article  PubMed  CAS  Google Scholar 

  7. Kim OY, Park HT, Dinh NTH, et al. Bacterial outer membrane vesicles suppress tumour by interferon-gamma-mediated antitumour response. Nat Commun 2017; 8: 626.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Zhu X, Du L, Feng J, Ling Y, Xu S. Clinicopathological and prognostic significance of serum cytokine levels in breast cancer. Clin Lab 2014; 60: 1145.

    PubMed  CAS  Google Scholar 

  9. Altman DG, McShane LM, Sauerbrei W, Taube SE. Reporting recommendations for tumour marker prognostic studies (REMARK): explanation and elaboration. PLoS Med 2012; 9: e1001216.

    Article  Google Scholar 

  10. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265.

    PubMed  CAS  Google Scholar 

  11. Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a newbio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 2004; 10: 7252.

    Article  PubMed  CAS  Google Scholar 

  12. Varela N, Munoz-Pinedo C, Ruiz-Ruiz C, Robledo G, Pedroso M, Lopez-Rivas A. Interferon-gamma sensitizes human myeloid leukemia cells to death receptor-mediated apoptosis by a pleiotropic mechanism. J Biol Chem 2001; 276: 17779.

    Article  PubMed  CAS  Google Scholar 

  13. Bellera CA, MacGrogan G, Debled M, de Lara CT, Brouste V, Mathoulin-Pelissier S. Variables with time-varying effects and the Cox model: some statistical concepts illustrated with a prognostic factor study in breast cancer. BMC Med Res Method 2010; 10: 20.

    Article  Google Scholar 

  14. Shankaran V, Ikeda H, Bruce AT, et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001; 410: 1107.

    Article  PubMed  CAS  Google Scholar 

  15. Marth C, Fiegl H, Zeimet AG, et al. Interferon-gamma expression is an independent prognostic factor in ovarian cancer. Am J Obstet Gynecol 2004; 191: 1598.

    Article  PubMed  CAS  Google Scholar 

  16. Razaghi A, Owens L, Heimann K. Reviewof the recombinant human interferon gamma as an immunotherapeutic: impacts of production platforms and glycosylation. J Biotechnol 2016; 240: 48.

    Article  PubMed  CAS  Google Scholar 

  17. Tartour E, Gey A, Sastre-Garau X, Lombard Surin I, Mosseri V, Fridman WH. Prognostic value of intratumoural interferon gamma messenger RNA expression in invasive cervical carcinomas. J Natl Cancer Inst 1998; 90: 287.

    Article  PubMed  CAS  Google Scholar 

  18. Schwanhausser B, Busse D, Li N, et al. Global quantification of mammalian gene expression control. Nature 2011; 473: 337.

    Article  PubMed  CAS  Google Scholar 

  19. Kruys V, Marinx O, Shaw G, Deschamps J, Huez G. Translational blockade imposed by cytokine-derived UA-rich sequences. Science 1989; 245: 852.

    Article  PubMed  CAS  Google Scholar 

  20. Perl K, Ushakov K, Pozniak Y, et al. Reduced changes in protein compared to mRNA levels across non-proliferating tissues. BMC Genomics 2017; 18: 305.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Kosti I, Jain N, Aran D, Butte AJ, Sirota M. Cross-tissue analysis of gene and protein expression in normal and cancer tissues. Sci Rep 2016; 6: 24799.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Chavey C, Bibeau F, Gourgou-Bourgade S, et al. Oestrogen receptor negative breast cancers exhibit high cytokine content. Breast Cancer Res 2007; 9: R15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Critchley-Thorne RJ, Simons DL, Yan N, et al. Impaired interferon signaling is a common immune defect in human cancer. Proc Natl Acad Sci U S A 2009; 106: 9010.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Guo Y, Yu P, Liu Z, et al. Prognostic and clinicopathological value of programmed death ligand-1 in breast cancer: a meta-analysis. PLoS One 2016; 11: e0156323.

    Google Scholar 

  25. Wu YY, Lin CW, Cheng KS, et al. Increased programmed deathligand-1 expression in human gastric epithelial cells in Helicobacter pylori infection. Clin Exp Immunol 2010; 161: 551.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Youngnak-Piboonratanakit P, Tsushima F, Otsuki N, et al. The expression of B7-H1 on keratinocytes in chronic inflammatory mucocutaneous disease and its regulatory role. Immunol Lett 2004; 94: 215.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia

    Nataša Todorović-Raković, Marko Radulovic, Tijana Vujasinović, Jelena Milovanović & Dragica Nikolić-Vukosavljević

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  1. Nataša Todorović-Raković
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  2. Marko Radulovic
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  3. Tijana Vujasinović
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  4. Jelena Milovanović
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  5. Dragica Nikolić-Vukosavljević
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Correspondence to Marko Radulovic.

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Todorović-Raković, N., Radulovic, M., Vujasinović, T. et al. The prognostic time dependence of intra-tumoural IFNγ mRNA and protein in patients with breast cancer followed for 14 years after surgery and radiotherapy, without subsequent systemic therapy. Eur Cytokine Netw 28, 151–156 (2017). https://doi.org/10.1684/ecn.2018.0402

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