Beyond the Abstract - Elevated levels of circulating IL-7 and IL-15 in patients with early stage prostate cancer, by Chantal Mengus, PhD, et al

BERKELEY, CA (UroToday.com) - Prostate cancer (PCA) is the second leading cause of cancer-related death in men with a death rate reaching 26.7% for 2001-2005 in the United States.[1]

A large body of literature based on histopathological, epidemiological, and molecular pathology data suggests that chronic inflammation might play an important role in prostate oncogenesis. To thoroughly evaluate the role of inflammation in PCA, it is critical to analyze molecular features and extent of inflammation in prostatic tissues with and without carcinoma.[2] We found that the expression of a number of genes encoding pro-inflammatory and homeostatic cytokines, including IL-6, IL-7 and IL-15 is detectable more frequently, and to a higher extent, in PCA as compared to Benign Prostatic Hyperplasia (BPH) tissues. In addition, we have reported for the first time that IL-7 and IL-15 serum levels are significantly higher in patients with PCA than in patients with BPH.[3] As expected,[4] IL-6 titres were also significantly higher in patients with PCA than in patients with BPH.

Common γ-chain receptor cytokines are known to have a major impact on cytotoxic T cell development, proliferation, and survival.[5,6] However, a recent study indicates that IL-2, IL-7 and IL-15 may also induce the expression of the “exhaustion” marker programmed death receptor 1 (PD-1) and of its ligands, PD-L1 and PD-L2, in CD8+ T cells from healthy donors, even at moderate cytokine concentrations.[7]In contrast, IL-21 has been shown to rescue exhausted T cells.[8-10] Notably PD-1 has been found to be expressed in CD8+ T cells infiltrating PCA.[11] However, no data are currently available regarding BPH infiltrating lymphocytes.

These findings urged us to verify whether the expression of the genes encoding these cytokines in prostatic tissues from patients bearing PCA or BPH is associated with the activation of cytotoxic T cells or, in contrast, with their exhaustion. We therefore evaluated the expression of PD-1 in tissue infiltrating CD8+ T cells from each group.

Preliminary results suggest that PD-1 is equally expressed in high percentages of CD8+ T cells infiltrating either PCA or BPH consistent with an “exhausted” CD8+ T cell phenotype in prostate tissues. These data support previous reports on the phenotypic characteristics of circulating and tissue infiltrating lymphocytes in chronic viral infections.[12-15] In this context, it is remarkable that the expression of the IL-21 gene, that is of the gene encoding the cytokine preventing PD-1 mediated T cell exhaustion[8,10,16] is, in our hands, equally rarely detectable in BPH or PCA.

Taken together these data indicate that, although both BPH and PCA are infiltrated by exhausted PD1+ CD8+ T cells, consistent with a chronic stimulation, local gene expression and systemic secretion of a number of soluble inflammation mediators are significantly increased in PCA, as compared to BPH.

 

References:

  1. Jemal A, Thun MJ, Ries LA, Howe HL, Weir HK, Center MM, Ward E, Wu XC, Eheman C, Anderson R et al.: Annual report to the nation on the status of cancer, 1975-2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 2008, 100:1672-1694.
  2. De Marzo AM, Platz EA, Sutcliffe S, Xu J, Gronberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG: Inflammation in prostate carcinogenesis. Nat Rev Cancer 2007, 7:256-269.
  3. Mengus C, Le MC, Trella E, Yousef K, Bubendorf L, Provenzano M, Bachmann A, Heberer M, Spagnoli GC, Wyler S: Elevated levels of circulating IL-7 and IL-15 in patients with early stage prostate cancer. J Transl Med 2011, 9:162.
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  7. Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, O'Shea MA, Fauci AS: The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 2008, 181:6738-6746.
  8. Elsaesser H, Sauer K, Brooks DG: IL-21 is required to control chronic viral infection. Science 2009, 324:1569-1572.
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  11. Sfanos KS, Bruno TC, Meeker AK, De Marzo AM, Isaacs WB, Drake CG: Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+. Prostate 2009, 69:1694-1703.
  12. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C et al.: PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006, 443:350-354.
  13. Franceschini D, Paroli M, Francavilla V, Videtta M, Morrone S, Labbadia G, Cerino A, Mondelli MU, Barnaba V: PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. J Clin Invest 2009, 119:551-564.
  14. Golden-Mason L, Palmer B, Klarquist J, Mengshol JA, Castelblanco N, Rosen HR: Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus-specific CD8+ T cells associated with reversible immune dysfunction. J Virol 2007, 81:9249-9258.
  15. Radziewicz H, Ibegbu CC, Fernandez ML, Workowski KA, Obideen K, Wehbi M, Hanson HL, Steinberg JP, Masopust D, Wherry EJ et al.: Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J Virol 2007, 81:2545-2553.
  16. Frohlich A, Kisielow J, Schmitz I, Freigang S, Shamshiev AT, Weber J, Marsland BJ, Oxenius A, Kopf M: IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science 2009, 324:1576-1580.

 

Written by:
Chantal Mengus, Clémentine le Magnen, Emanuele Trella, Kawa Yousef, Lukas Bubendorf, Maurizio Provenzano, Alexander Bachmann, Michael Heberer, Giulio C. Spagnoli and Stephen Wyler as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Elevated levels of circulating IL-7 and IL-15 in patients with early stage prostate cancer - Abstract

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