Cancer Immunology, Immunotherapy

, Volume 66, Issue 9, pp 1143–1151 | Cite as

FKBP51s signature in peripheral blood mononuclear cells of melanoma patients as a possible predictive factor for immunotherapy

  • Simona Romano
  • Ester Simeone
  • Anna D’Angelillo
  • Paolo D’Arrigo
  • Michele Russo
  • Mario Capasso
  • Vito Alessandro Lasorsa
  • Nicola Zambrano
  • Paolo A. AsciertoEmail author
  • Maria Fiammetta RomanoEmail author
Original Article


The inhibitory immune checkpoint PD-L1/PD1 promotes the alternative splicing of the FKBP5 gene, resulting in increased expression of its variant 4 in the peripheral blood mononuclear cells of melanoma patients. The variant 4 transcript is translated into the truncated FKBP51s protein. Given the importance of co-inhibitory signalling in tumour immune escape, here we tested the potential for using FKBP51s expression to predict immunotherapy outcomes. To do this, we immunophenotyped PBMCs from 118 melanoma patients and 77 age- and sex-matched healthy controls. Blood samples were collected before patients underwent ipilimumab treatment. In 64 of the 118 patients, FKBP51s expression was also assessed in regulatory T cells (Tregs). We found that each PBMC subset analysed contained an FKBP51spos fraction, and that this fraction was greater in the melanoma patients than healthy controls. In CD4 T lymphocytes, the FKBP51sneg fraction was significantly impaired. Tregs count was increased in melanoma patients, which is in line with previous studies. Also, by analyses of FKBP51s in Tregs, we identified a subgroup of ipilimumab nonresponder patients (p = 0.002). In conclusion, FKBP51s-based immunophenotyping of melanoma patients revealed several profiles related to a negative immune regulatory control and identified an unknown Treg subset. These findings are likely to be useful in the selection of the patients that are candidate for immunotherapy.


Melanoma Immunophenotype Ipilimumab Tregs FKBP5 









FK506 binding protein


Mammalian target of rapamycin








Regulatory T cell



We thank the Cardiovascular Service for supporting our research. We also thank Prof. Tommaso Russo (Dept. Molecular Medicine and Medical Biotechnology, Federico II University of Naples) for helpful discussion and advice.

Compliance with ethical standards

Conflict of interest

Simona Romano, Anna D’Angelillo, and Maria Fiammetta Romano have intellectual property rights (Patent No. 1 419 465, RM2013A000406, 11/7/2013 “A tumor biomarker, in particular of melanoma”). Paolo Antonio Ascierto has received research grants from Bristol-Myers Squibb, Roche-Genentech, and Array and has had a consultant/advisory role for Bristol-Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Amgen, Array, Merck, and Pierre-Fabre. The other authors declare no conflict of interest.

Supplementary material

262_2017_2004_MOESM1_ESM.pdf (8.5 mb)
Supplementary material 1 (PDF 8709 kb)


  1. 1.
    Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C et al (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412–7420. doi: 10.1158/1078-0432.CCR-09-1624 CrossRefPubMedGoogle Scholar
  2. 2.
    Romano MF, Avellino R, Petrella A, Bisogni R, Romano S, Venuta S (2004) Rapamycin inhibits doxorubicin-induced NF-kappaB/Rel nuclear activity and enhances the apoptosis of melanoma cells. Eur J Cancer 40:2829–2836. doi: 10.1016/j.ejca.2004.08.017 CrossRefPubMedGoogle Scholar
  3. 3.
    Romano S, D’Angelillo A, Pacelli R, Staibano S, De Luna E, Bisogni R et al (2010) Role of FK506 binding protein 51 [FKBP51] in the control of apoptosis of irradiated melanoma cells. Cell Death Differ 17:145–157. doi: 10.1038/cdd.2009.115 CrossRefPubMedGoogle Scholar
  4. 4.
    Baughman G, Wiederrecht GJ, Faith Campbell N, Martin MM, Bourgeois S (1995) FKBP51, a novel T-cell specific immunophilin capable of calcineurin inhibition. Mol Cell Biol 15:4395–4402. doi: 10.1128/MCB.15.8.4395 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Dornan J, Taylor P, Walkinshaw MD (2003) Structures of immunophilins and their ligand complexes. Curr Top Med Chem 3:1392–1409. doi: 10.2174/1568026033451899 CrossRefPubMedGoogle Scholar
  6. 6.
    Fischer G, Aumüller T (2003) Regulation of peptide bond cis/trans isomerization by enzyme catalysis and its implication in physiological processes. Rev Physiol Biochem Pharmacol 148:105–150. doi: 10.1007/s10254-003-0011-3 CrossRefPubMedGoogle Scholar
  7. 7.
    Romano S, D’Angelillo A, Romano MF (2015) Pleiotropic roles in cancer biology for multifaceted proteins FKBPs. Biochim Biophys Acta 1850:2061–2068. doi: 10.1016/j.bbagen.2015.01.004 (Review) CrossRefPubMedGoogle Scholar
  8. 8.
    Romano S, Xiao Y, Nakaya M, D’Angelillo A, Chang M, Jin J et al (2015) FKBP51 employs both scaffold and isomerase functions to promote NF-κB activation in melanoma. Nucleic Acids Res 43:6983–6993. doi: 10.1093/nar/gkv615 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Romano S, D’Angelillo A, D’Arrigo P, Staibano S, Greco A, Brunetti A et al (2014) FKBP51 increases the tumour promoter potential of TGF-beta. Clin Transl Med 3:1. doi: 10.1186/2001-1326-3-1 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Romano S, D’Angelillo A, Staibano S, Simeone E, D’Arrigo P, Ascierto PA et al (2015) Immunomodulatory pathways regulate expression of a spliced FKBP51 isoform in lymphocytes of melanoma patients. Pigment Cell Melanoma Res 28:442–452. doi: 10.1111/pcmr.12378 CrossRefPubMedGoogle Scholar
  11. 11.
    Romano MF, D’Angelillo A, Ascierto PA, Simeone E, Staibano S, D’Arrigo P et al (2015) Expansion of a lymphocyte subset expressing a spliced FKBP51 isoform in melanoma patients. J Clin Oncol. doi: 10.1200/jco.2015.33.15_suppl.e20070 (Abstract) Google Scholar
  12. 12.
    Simeone E, Gentilcore G, Giannarelli D, Grimaldi AM, Caracò C, Curvietto M et al (2014) Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother 63:675–683. doi: 10.1007/s00262-014-1545-8 CrossRefPubMedGoogle Scholar
  13. 13.
    Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson CC (2010) Regulatory T cells in cancer. Adv Cancer Res 107:57–117. doi: 10.1016/S0065-230X(10)07003-X CrossRefPubMedGoogle Scholar
  14. 14.
    Martens A, Wistuba-Hamprecht K, Geukes Foppen M, Yuan J, Postow MA, Wong P et al (2016) Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res 22:2908–2918. doi: 10.1158/1078-0432.CCR-15-2412 CrossRefPubMedGoogle Scholar
  15. 15.
    Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H (2013) mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499:485–490. doi: 10.1038/nature12297 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Diem S, Kasenda B, Spain L, Martin-Liberal J, Marconcini R, Gore M, Larkin J (2016) Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma. Br J Cancer 114:256–261. doi: 10.1038/bjc.2015.467 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Jiang Y, Li Y, Zhu B (2015) T-cell exhaustion in the tumor microenvironment. Cell Death Dis 6:e1792. doi: 10.1038/cddis.2015.162 (Review) CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Topalian SL, Taube JM, Anders RA, Pardoll DM (2016) Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16:275–287. doi: 10.1038/nrc.2016.36 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Robert L, Harview C, Emerson R, Wang X, Mok S, Homet B et al (2014) Distinct immunological mechanisms of CTLA-4 and PD-1 blockade revealed by analyzing TCR usage in blood lymphocytes. Oncoimmunology 3:e29244. doi: 10.4161/onci.29244 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Maker AV, Attia P, Rosenberg SA (2005) Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J Immunol 175:7746–7754. doi: 10.4049/jimmunol.175.11.7746 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ku GY, Yuan J, Page DB, Schroeder SE, Panageas KS, Carvajal RD et al (2010) Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 116:1767–1775. doi: 10.1002/cncr.24951 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Hannani D, Vétizou M, Enot D, Rusakiewicz S, Chaput N, Klatzmann D et al (2015) Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25. Cell Res 25:208–224. doi: 10.1038/cr.2015.3 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Sharma P, Allison JP (2015) Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161:205–214. doi: 10.1016/j.cell.2015.03.030 CrossRefPubMedGoogle Scholar
  24. 24.
    Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK et al (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206:3015–3029. doi: 10.1084/jem.20090847 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Duhen T, Duhen R, Lanzavecchia A, Sallusto F, Campbell DJ (2012) Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood 119:4430–4440. doi: 10.1182/blood-2011-11-392324 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Department of Molecular Medicine and Medical BiotechnologiesFederico II UniversityNaplesItaly
  2. 2.Melanoma Cancer Immunotherapy and Innovative Therapy UnitIstituto Nazionale Tumori Fondazione “G. Pascale”NaplesItaly
  3. 3.CEINGE Biotecnologie AvanzateNaplesItaly

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