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

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Abstract

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.

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Abbreviations

APC:

Allophycocyanin

C:

Cluster

FAM:

5-Carboxyfluorescein

FKBP:

FK506 binding protein

mTOR:

Mammalian target of rapamycin

NR:

Nonresponder

p-mTOR:

Phosphorylated-mTOR

R:

Responder

Treg:

Regulatory T cell

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Via Pansini, 5, 80131, Naples, Italy

    Simona Romano, Anna D’Angelillo, Paolo D’Arrigo, Michele Russo, Mario Capasso, Vito Alessandro Lasorsa, Nicola Zambrano & Maria Fiammetta Romano

  2. Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione “G. Pascale”, Via Mariano Semmola, 80131, Naples, Italy

    Ester Simeone & Paolo A. Ascierto

  3. CEINGE Biotecnologie Avanzate, Naples, Italy

    Mario Capasso, Vito Alessandro Lasorsa & Nicola Zambrano

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  1. Simona Romano
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  2. Ester Simeone
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  3. Anna D’Angelillo
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  4. Paolo D’Arrigo
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  5. Michele Russo
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  9. Paolo A. Ascierto
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  10. Maria Fiammetta Romano
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Corresponding authors

Correspondence to Paolo A. Ascierto or Maria Fiammetta Romano.

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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.

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Romano, S., Simeone, E., D’Angelillo, A. et al. FKBP51s signature in peripheral blood mononuclear cells of melanoma patients as a possible predictive factor for immunotherapy. Cancer Immunol Immunother 66, 1143–1151 (2017). https://doi.org/10.1007/s00262-017-2004-0

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  • DOI: https://doi.org/10.1007/s00262-017-2004-0

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