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Impact of the immunomodulating peptide thymosin alpha 1 on multiple myeloma and immune recovery after hematopoietic stem cell transplantation

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Abstract

Multiple myeloma (MM) is characterized by the accumulation of monoclonal plasma cells in the bone marrow and causes several immune alterations in patients. Thymosin α1 (Tα1) is a thymic peptide that has been associated with immuno-stimulating properties. In addition, this peptide exerts anti-tumor effects in several cancer types. Beneficial effects of Tα1 administration have also been shown on immune reconstitution after hematopoietic stem cell transplantation (HSCT), a current treatment modality in hematological malignancies including MM. In this study, we observed a slight reduction in the proliferation of murine and human MM cell lines in the presence of Tα1 in vitro. However, using two immunocompetent murine MM models (5TGM1 and MOPC315.BM), we did not observe any impact of Tα1 administration on MM development in vivo. Furthermore, no beneficial effects of Tα1 treatment were observed on lymphocyte immune reconstitution after transfusion of human hematopoietic stem cells into immunodeficient mice. In conclusion, despite direct effects of Tα1 on human MM cell line proliferation in vitro, Tα1 did not exert anti-myeloma effects in vivo in the two murine models tested. Moreover, Tα1 failed to improve immune recovery in a xenogeneic HSCT model.

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Abbreviations

Allo-HSCT:

Allogeneic hematopoietic stem cell transplantation

Allo-MLR:

Allogeneic mixed lymphocyte reaction

Auto-HSCT:

Autologous hematopoietic stem cell transplantation

BM:

Bone marrow

CTL:

Cytotoxic T lymphocytes

FBS:

Fetal bovine serum

GvHD:

Graft-versus-host disease

HSCT:

Hematopoietic stem cell transplantation

IL:

Interleukin

i.v.:

Intravenous

MHC:

Major histocompatibility complex

MM:

Multiple myeloma

NSCLC:

Non-small cell lung carcinoma

NSG:

NOD/SCID/IL2rγnull

PBS:

Phosphate-buffered saline

RTE:

Recent thymic emigrants

Tα1:

Thymosin α1

TCM:

Central memory T cells

TEM:

Effector memory T cells

TEMRA:

CD45RA re-expressing effector memory T cells

Treg:

Regulatory T cells

References

  1. Caers J, Vande broek I, De Raeve H, Michaux L, Trullemans F, Schots R, Van Camp B, Vanderkerken K (2008) Multiple myeloma—an update on diagnosis and treatment. Eur J Haematol 81:329–343

    CAS  PubMed  Google Scholar 

  2. Binsfeld M, Fostier K, Muller J, Baron F, Schots R, Beguin Y, Heusschen R, Caers J (2014) Cellular immunotherapy in multiple myeloma: lessons from preclinical models. Biochim Biophys Acta 1846:392–404

    CAS  PubMed  Google Scholar 

  3. Goldstein AL, Low TL, McAdoo M, McClure J, Thurman GB, Rossio J, Lai CY, Chang D, Wang SS, Harvey C, Ramel AH, Meienhofer J (1977) Thymosin alpha 1: isolation and sequence analysis of an immunologically active thymic polypeptide. Proc Natl Acad Sci U S A 74:725–729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sarandeses CS, Covelo G, Diaz-Jullien C, Freire M (2003) Prothymosin alpha is processed to thymosin alpha 1 and thymosin alpha 11 by a lysosomal asparaginyl endopeptidase. J Biol Chem 278:13286–13293

    Article  CAS  PubMed  Google Scholar 

  5. Favalli C, Jezzi T, Mastino A, Rinaldi-Garaci C, Riccardi C, Garaci E (1985) Modulation of natural killer activity by thymosin alpha 1 and interferon. Cancer Immunol Immunother 20:189–192

    Article  CAS  PubMed  Google Scholar 

  6. Bozza S, Gaziano R, Bonifazi P, Zelante T, Pitzurra L, Montagnoli C, Moretti S, Castronari R, Sinibaldi P, Rasi G, Garaci E, Bistoni F, Romani L (2007) Thymosin alpha 1 activates the TLR9/MyD88/IRF7-dependent murine cytomegalovirus sensing for induction of anti-viral responses in vivo. Int Immunol 19:1261–1270

    Article  CAS  PubMed  Google Scholar 

  7. Romani L, Bistoni F, Gaziano R, Bozza S, Montagnoli C, Perruccio K, Pitzurra L, Bellocchio S, Velardi A, Rasi G, Di Francesco P, Garaci E (2004) Thymosin alpha 1 activates dendritic cells for antifungal Th1 resistance through toll-like receptor signaling. Blood 103:4232–4239

    Article  CAS  PubMed  Google Scholar 

  8. Sztein MB, Serrate SA (1989) Characterization of the immunoregulatory properties of thymosin alpha 1 on interleukin-2 production and interleukin-2 receptor expression in normal human lymphocytes. Int J Immunopharmacol 11:789–800

    Article  CAS  PubMed  Google Scholar 

  9. Baumann CA, Badamchian M, Goldstein AL (1997) Thymosin alpha 1 antagonizes dexamethasone and CD3-induced apoptosis of CD4+ CD8+ thymocytes through the activation of cAMP and protein kinase C dependent second messenger pathways. Mech Ageing Dev 94:85–101

    Article  CAS  PubMed  Google Scholar 

  10. Knutsen AP, Freeman JJ, Mueller KR, Roodman ST, Bouhasin JD (1999) Thymosin-alpha 1 stimulates maturation of CD34+ stem cells into CD3+4+ cells in an in vitro thymic epithelia organ coculture model. Int J Immunopharmacol 21:15–26

    Article  CAS  PubMed  Google Scholar 

  11. Lao X, Liu M, Chen J, Zheng H (2013) A tumor-penetrating peptide modification enhances the antitumor activity of thymosin alpha 1. Plos One 8:e72242

    Article  PubMed  PubMed Central  Google Scholar 

  12. Xue XC, Yan Z, Li WN, Li M, Qin X, Zhang C, Hao Q, Wang ZL, Zhao N, Zhang W, Zhang YQ (2013) Construction, expression, and characterization of thymosin alpha 1 tandem repeats in Escherichia coli. Biomed Res Int 2013:720285

    PubMed  PubMed Central  Google Scholar 

  13. Perruccio K, Bonifazi P, Topini F, Tosti A, Bozza S, Aloisi T, Carotti A, Aversa F, Martelli MF, Romani L, Velardi A (2010) Thymosin alpha 1 to harness immunity to pathogens after haploidentical hematopoietic transplantation. Ann N Y Acad Sci 1194:153–161

    Article  CAS  PubMed  Google Scholar 

  14. Giuliani C, Napolitano G, Mastino A, Di Vincenzo S, D’Agostini C, Grelli S, Bucci I, Singer DS, Kohn LD, Monaco F, Garaci E, Favalli C (2000) Thymosin-alpha 1 regulates MHC class I expression in FRTL-5 cells at transcriptional level. Eur J Immunol 30:778–786

    Article  CAS  PubMed  Google Scholar 

  15. Bubenik J (2004) MHC class I down-regulation: tumour escape from immune surveillance? (review). Int J Oncol 25:487–491

    CAS  PubMed  Google Scholar 

  16. Moody TW, Leyton J, Zia F, Tuthill C, Badamchian M, Goldstein AL (2000) Thymosin alpha1 is chemopreventive for lung adenoma formation in A/J mice. Cancer Lett 155:121–127

    Article  CAS  PubMed  Google Scholar 

  17. Moody TW, Tuthill C, Badamchian M, Goldstein AL (2002) Thymosin alpha 1 inhibits mammary carcinogenesis in Fisher rats. Peptides 23:1011–1014

    Article  CAS  PubMed  Google Scholar 

  18. Moody TW, Fagarasan M, Zia F, Cesnjaj M, Goldstein AL (1993) Thymosin alpha 1 down-regulates the growth of human non-small cell lung cancer cells in vitro and in vivo. Cancer Res 53:5214–5218

    CAS  PubMed  Google Scholar 

  19. Schulof RS, Lloyd MJ, Cleary PA, Palaszynski SR, Mai DA, Cox JW Jr, Alabaster O, Goldstein AL (1985) A randomized trial to evaluate the immunorestorative properties of synthetic thymosin-alpha 1 in patients with lung cancer. J Biol Response Mod 4:147–158

    CAS  PubMed  Google Scholar 

  20. Sungarian A, Cielo D, Sampath P, Bowling N, Moskal P, Wands JR, de la Monte SM (2009) Potential role of thymosin-alpha 1 adjuvant therapy for glioblastoma. J Oncol 2009:302084

    Article  PubMed  PubMed Central  Google Scholar 

  21. Pica F, Fraschetti M, Matteucci C, Tuthill C, Rasi G (1998) High doses of thymosin alpha 1 enhance the anti-tumor efficacy of combination chemo-immunotherapy for murine B16 melanoma. Anticancer Res 18:3571–3578

    CAS  PubMed  Google Scholar 

  22. Maio M, Mackiewicz A, Testori A, Trefzer U, Ferraresi V, Jassem J, Garbe C, Lesimple T, Guillot B, Gascon P, Gilde K, Camerini R, Cognetti F, Thymosin Melanoma Investigation G (2010) Large randomized study of thymosin alpha 1, interferon alfa, or both in combination with dacarbazine in patients with metastatic melanoma. J Clin Oncol 28:1780–1787

    Article  CAS  PubMed  Google Scholar 

  23. Rasi G, Silecchia G, Sinibaldi-Vallebona P, Spaziani E, Pierimarchi P, Sivilia M, Tremiterra S, Garaci E (1994) Anti-tumor effect of combined treatment with thymosin alpha 1 and interleukin-2 after 5-fluorouracil in liver metastases from colorectal cancer in rats. Int J Cancer 57:701–705

    Article  CAS  PubMed  Google Scholar 

  24. Silecchia G, Guarino E, Sinibaldi-Vallebona P, Pierimarchi P, Restuccia A, Spaziani E, Bernard P, Tuthill C, Garaci E, Rasi G (1999) Efficacy of repeated cycles of chemo-immunotherapy with thymosin alpha 1 and interleukin-2 after intraperitoneal 5-fluorouracil delivery. Cancer Immunol Immunother 48:172–178

    Article  CAS  PubMed  Google Scholar 

  25. Lauritzsen GF, Bogen B (1993) The role of idiotype-specific, CD4+ T cells in tumor resistance against major histocompatibility complex class II molecule negative plasmacytoma cells. Cell Immunol 148:177–188

    Article  CAS  PubMed  Google Scholar 

  26. Hofgaard PO, Jodal HC, Bommert K, Huard B, Caers J, Carlsen H, Schwarzer R, Schunemann N, Jundt F, Lindeberg MM, Bogen B (2012) A novel mouse model for multiple myeloma (MOPC315.BM) that allows noninvasive spatiotemporal detection of osteolytic disease. Plos One 7:e51892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Garrett IR, Dallas S, Radl J, Mundy GR (1997) A murine model of human myeloma bone disease. Bone 20:515–520

    Article  CAS  PubMed  Google Scholar 

  28. Oyajobi BO, Munoz S, Kakonen R, Williams PJ, Gupta A, Wideman CL, Story B, Grubbs B, Armstrong A, Dougall WC, Garrett IR, Mundy GR (2007) Detection of myeloma in skeleton of mice by whole-body optical fluorescence imaging. Mol Cancer Ther 6:1701–1708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Binsfeld M, Beguin Y, Belle L, Otjacques E, Hannon M, Briquet A, Heusschen R, Drion P, Zilberberg J, Bogen B, Baron F, Caers J (2014) Establishment of a murine graft-versus-myeloma model using allogeneic stem cell transplantation. Plos One 9:e113764

    Article  PubMed  PubMed Central  Google Scholar 

  30. Otjacques E, Binsfeld M, Rocks N, Blacher S, Vanderkerken K, Noel A, Beguin Y, Cataldo D, Caers J (2013) Mithramycin exerts an anti-myeloma effect and displays anti-angiogenic effects through up-regulation of anti-angiogenic factors. Plos One 8:e62818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G, Watanabe T, Akashi K, Shultz LD, Harada M (2005) Development of functional human blood and immune systems in NOD/SCID/IL2 receptor gamma chain(null) mice. Blood 106:1565–1573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li M, Feurino LW, Li F, Wang H, Zhai Q, Fisher WE, Chen C, Yao Q (2007) Thymosin alpha 1 stimulates cell proliferation by activating ERK1/2, JNK, and increasing cytokine secretion in human pancreatic cancer cells. Cancer Lett 248:58–67

    Article  CAS  PubMed  Google Scholar 

  33. Corthay A, Skovseth DK, Lundin KU, Rosjo E, Omholt H, Hofgaard PO, Haraldsen G, Bogen B (2005) Primary antitumor immune response mediated by CD4+ T cells. Immunity 22:371–383

    Article  CAS  PubMed  Google Scholar 

  34. Ding JH, Wang LL, Chen Z, Wang J, Yu ZP, Zhao G, Chen BA (2013) The role of T alpha 1 on the infective patients after hematopoietic stem cell transplantation. Int J Hematol 97:280–283

    Article  CAS  PubMed  Google Scholar 

  35. Wang B, He F, Lin Y, Huang M, Zhou SF (2007) Effect of recombinant human thymosin-alpha 1, an immuno-modulating peptide with 28 amino acids, on the activity of cytochrome P450s. Drug Metab Lett 1:199–204

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Dr. Cynthia Tuthill (Sciclone Pharmaceuticals) for providing Tα1. They are grateful to Sophie Dubois, Coline Daulne, Amélie Halleux and Nadine Wanten (GIGA-Research Hematology and Laboratory of Cell and Gene Therapy, University of Liège and CHU of Liège, Belgium) for excellent technical assistance. Thanks also to Prof. A. Gothot (Hematology laboratory, CHU de Liège, Belgium) for his help in quantitative analysis of immune cells, to the laboratory of tumor and developmental biology (University of Liège, Belgium) for their help in bioluminescence studies, to Professors G. Mundy, C. M. Edwards (Vanderbilt University, Nashville, TN, USA) and B. Bogen (University of Oslo, Norway) for providing murine myeloma cell lines, to Prof. H. Jernberg-Wiklund (Uppsala University, Sweden) for providing human MM cell lines, and finally, thanks to the «Imaging and flow cytometry platform» (GIGA-Research, University of Liège, Belgium) for the use of FACS Canto II and technical assistance. This work has been supported by Télévie grants from the Belgian “Fonds National de la Recherche Scientifique” (FNRS), by grants from the “Fonds Léon Frédéricq,” the “Fondation contre le Cancer” and by special research grants from the University of Liège.

Conflict of interest

There are no conflicts of interest for any of the authors.

Author information

Authors and Affiliations

  1. Laboratory of Hematology, GIGA-Research, University of Liège, Bat. B34, CHU of Liège, Avenue de l’Hôpital, 1, 4000, Liège, Belgium

    Marilène Binsfeld, Muriel Hannon, Eléonore Otjacques, Yves Beguin, Frédéric Baron & Jo Caers

  2. Laboratory of Genetics of Autoimmunity, Katholieke Universiteit Leuven, 3000, Louvain, Belgium

    Stéphanie Humblet-Baron

  3. Laboratory of Cell and Gene Therapy, University of Liège and CHU of Liège, 4000, Liège, Belgium

    Etienne Baudoux & Yves Beguin

Authors
  1. Marilène Binsfeld
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  2. Muriel Hannon
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  3. Eléonore Otjacques
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  4. Stéphanie Humblet-Baron
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  5. Etienne Baudoux
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  6. Yves Beguin
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  7. Frédéric Baron
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  8. Jo Caers
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Corresponding author

Correspondence to Marilène Binsfeld.

Additional information

Previous publication of this work as poster and abstract

Binsfeld M, Otjacques E, Hannon M, Dubois S, Beguin Y, Baron F, Caers J. The immunomodulating peptide thymosin alpha 1 has no effects on multiple myeloma evolution and on immune reconstitution. 28th General Annual Meeting of the Belgian Hematological Society (BHS). Gent (Belgium), 24th–26th January 2013. Abstract Book p. 41, P73.

Binsfeld M, Hannon M, Humblet-Baron S, Beguin Y, Baron F, Caers J. Effects of the immunomodulating peptide thymosin alpha 1 in multiple myeloma and immune reconstitution after hematopoietic stem cell transplantation in murine models. 30th General Annual Meeting of the Belgian Hematological Society (BHS) La Hulpe (Belgium), 31st January–1st February 2015. Abstract Book p. 29, P3.14.

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Binsfeld, M., Hannon, M., Otjacques, E. et al. Impact of the immunomodulating peptide thymosin alpha 1 on multiple myeloma and immune recovery after hematopoietic stem cell transplantation. Cancer Immunol Immunother 64, 989–998 (2015). https://doi.org/10.1007/s00262-015-1708-2

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