Abstract

The predominant usage of VH4-34 and V3-21 and reports of stereotyped CDR3s suggest a shared antigenic target of B-cell receptors (BCR) from mantle cell lymphomas (MCL). To identify the target antigens of MCL–BCRs, BCRs from 21 patients and seven MCL cell lines were recombinantly expressed and used for antigen screening. The BCRs from 8/21 patients and 2/7 MCL cell lines reacted specifically with the autoantigen low-density lipoprotein receptor-related protein-associated protein 1 (LRPAP1). High-titered and light chain-restricted anti-LRPAP1 serum antibodies were found in MCL patients, but not in controls. LRPAP1 induced proliferation by BCR pathway activation, while an LRPAP1–ETA′ toxin-conjugate specifically killed MCL cells with LRPAP1-specific BCRs. Our results suggest a role of LRPAP1 in lymphomagenesis and maintenance of a considerable proportion of MCL cases by chronic autoantigenic stimulation, likely evolving from a chronic autoreactive B-cell response. Importantly, LRPAP1 can be used for a novel therapeutic approach that targets MCL with LRPAP1-reactive BCRs with high specificity.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

In Memoriam of Professor Dr. Michael Pfreundschuh.

References

  1. 1.

    Queirós AC, Beekman R, Vilarrasa-Blasi R, Duran-Ferrer M, Clot G, Merkel A, et al. Decoding the DNA methylome of mantle cell lymphoma in the light of the entire B cell lineage. Cancer Cell. 2016;30:806–21.

  2. 2.

    Kienle D, Kröber A, Katzenberger T, Ott G, Leupolt E, Barth TFE, et al. VH mutation status and VDJ rearrangement structure in mantle cell lymphoma: correlation with genomic aberrations, clinical characteristics, and outcome. Blood. 2003;102:3003–9.

  3. 3.

    Hadzidimitriou A, Agathangelidis A, Darzentas N, Murray F, Delfau-Larue MH, Pedersen LB, et al. Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases. Blood. 2011;118:3088–95.

  4. 4.

    Walsh SH, Thorsélius M, Johnson A, Söderberg O, Jerkeman M, Björck E, et al. Mutated VH genes and preferential VH3-21 use define new subsets of mantle cell lymphoma. Blood. 2003;101:4047–54.

  5. 5.

    Dameshek W, Schwartz RS. Leukemia and auto-immunization—some possible relationships. Blood. 1959;14:1151–8.

  6. 6.

    Saba NS, Liu D, Herman SEM, Underbayev C, Tian X, Behrend D, et al. Pathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma. Blood. 2016;128:82–93.

  7. 7.

    Myklebust JH, Brody J, Kohrt HE, Kolstad A, Czerwinski DK, Wälchli S, et al. Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling. Blood. 2017;129:759–70.

  8. 8.

    Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507–16.

  9. 9.

    Kahl BS, Spurgeon SE, Furman RR, Flinn IW, Coutre SE, Brown JR, et al. A phase 1 study of the PI3Kδ inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood. 2014;123:3398–405.

  10. 10.

    Eskelund CW, Dahl C, Hansen JW, Westman M, Kolstad A, Pedersen LB, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017 Oct 26;130(17):1903-1910. https://doi.org/10.1182/blood-2017-04-779736. Epub 2017 Aug 17.

  11. 11.

    Stevenson FK, Smith GJ, North J, Hamblin TJ, Glennie MJ. Identification of normal B-cell counterparts of neoplastic cells which secrete cold agglutinins of anti-I and anti-i specificity. Br J Haematol. 1989;72:9–15.

  12. 12.

    Martin T, Weber JC, Levallois H, Labouret N, Soley A, Koenig S, et al. Salivary gland lymphomas in patients with Sjogren’s syndrome may frequently develop from rheumatoid factor B cells. Arthritis Rheum. 2000;43:908–16.

  13. 13.

    Preuss KD, Pfreundschuh M, Fadle N, Regitz E, Kubuschok B. Sumoylated HSP90 is a dominantly inherited plasma cell dyscrasias risk factor. J Clin Invest. 2015;125:316–23.

  14. 14.

    Preuss KD, Pfreundschuh M, Ahlgrimm M, Fadle N, Regitz E, Murawski N, et al. A frequent target of paraproteins in the sera of patients with multiple myeloma and MGUS. Int J Cancer. 2009;125:656–61.

  15. 15.

    Khodadoust MS, Olsson N, Wagar LE, Haabeth OAW, Chen B, Swaminathan K, et al. Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens. Nature. 2017;543:723–7.

  16. 16.

    Fichtner M, Spies E, Seismann H, Riecken K, Engels N, Gösch B, et al. Complementarity determining region-independent recognition of a superantigen by B-cell antigen receptors of mantle cell lymphoma. Haematologica. 2016;101:e378–81.

  17. 17.

    Kueppers R, Schneider M, Hansmann ML. Laser-based microdissection of single cells from tissue sections and PCR analysis of rearranged immunoglobulin genes from isolated normal and malignant human B cells. Methods Mol Biol. 2013;971:49–63.

  18. 18.

    de Haard HJ, van Neer N,Reurs A,Hufton SE,Roovers RC,Henderikx P, et al. A large non-immunized human Fab fragment phage library that permits rapid isolation and kinetic analysis of high affinity antibodies. J Biol Chem. 1999;274:18218–30.

  19. 19.

    Thurner L, Müller A, Cérutti M, Martin T, Pasquali JL, Gross WL, et al. Wegener’s granuloma harbors B lymphocytes with specificities against a proinflammatory transmembrane protein and a tetraspanin. J Autoimmun. 2011;36:87–90.

  20. 20.

    Preuss KD, Pfreundschuh M, Fadle N, Regitz E, Raudies S, Murwaski N, et al. Hyperphosphorylation of autoantigenic targets of paraproteins is due to inactivation of PP2A. Blood. 2011;118:3340–6.

  21. 21.

    Nachreiner T, Kampmeier F, Thepen T, Fischer R, Barth S, Stocker M. Depletion of autoreactive B-lymphocytes by a recombinant myelin oligodendrocyte glycoprotein-based immunotoxin. J Neuroimmunol. 2008;195:28–35.

  22. 22.

    Hartmann S, Agostinelli C, Klapper W, Korkolopoulou P, Koch K, Marafioti T, et al. Revising the historical collection of epithelioid cell-rich lymphomas of the Kiel Lymph Node Registry: what is Lennert’s lymphoma nowadays? Histopathology. 2011;59:1173–82.

  23. 23.

    Bornkamm GW, Berens C, Kuklik-Roos C, Bechet JM, Laux G, Bachl J, et al. Stringent doxycycline-dependent control of gene activities using an episomal one-vector system. Nucleic Acids Res. 2005;33:1–11.

  24. 24.

    Freitag J, Heink S, Roth E, Wittmann J, Jäck HM, Kamradt T. Towards the generation of B-cell receptor retrogenic mice. PLoS One. 2014;9. https://doi.org/10.1371/journal.pone.0109199.

  25. 25.

    Chiron D, Di Liberto M, Martin P, Huang X, Sharman J, Blecua P, et al. Cell-cycle reprogramming for Pi3K inhibition overrides a relapse-specific C481s BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 2014;4:1022–35.

  26. 26.

    Korenberg JR, Argraves KM, Chen XN, Tran H, Strickland DK, Argraves WS. Chromosomal localization of human genes for the LDL receptor family member glycoprotein 330 (LRP2) and its associated protein RAP (LRPAP1). Genomics. 1994;22:88–93.

  27. 27.

    Herz J, Goldstein JL, Strickland DK, Ho YK, Brown MS. 39-kDa protein modulates binding of ligands to low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. J Biol Chem. 1991;266:21232–8.

  28. 28.

    Williams SE, Ashcom JD, Argraves WS, Strickland DK. A novel mechanism for controlling the activity of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein. Multiple regulatory sites for 39-kDa receptor-associated protein. J Biol Chem. 1992;267:9035–40.

  29. 29.

    Striekland DK, Ashcom JD, Williams S, Battey F, Behre E, McTigue K, et al. Primary structure of alpha 2-macroglobulin receptor-associated protein. Human homologue of a Heymann nephritis antigen. J Biol Chem. 1991;266:13364–9.

  30. 30.

    Orlando RA, Farquhar MG. Functional domains of the receptor-associated protein (RAP). Proc Natl Acad Sci USA. 1994;91:3161–5.

  31. 31.

    Doronina SO, Toki BE, Torgov MY, Mendelsohn BA, Cerveny CG, Chace DF, et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat. Biotechnol. 2003. https://doi.org/10.1038/nbt832.

  32. 32.

    Oflazoglu E, Kissler KM, Sievers EL, Grewal IS, Gerber HP. Combination of the anti-CD30-auristatin-E antibody-drug conjugate (SGN-35) with chemotherapy improves antitumour activity in Hodgkin lymphoma. Br J Haematol. 2008. https://doi.org/10.1111/j.1365-2141.2008.07146.x

  33. 33.

    Torchia J, Weiskopf K, Levy R. Targeting lymphoma with precision using semisynthetic anti-idiotype peptibodies. Proc Natl Acad Sci USA. 2016. https://doi.org/10.1073/pnas.1603335113.

  34. 34.

    Ellebrecht CT, Bhoj VG, Nace A, Choi EJ, Mao X, Cho MJ, et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science. 2016;6756:1–11.

Download references

Acknowledgments

We are grateful to the entire team of the José-Carreras-Center for Immuno- and Gene Therapy and the Department of Internal Medicine I of Saarland University Medical School for their continuous logistic and intellectual support. This work was supported by a grant from Wilhelm-Sander-Stiftung (a charity foundation in Munich, Germany).

Author contributions

LT, SH, KDP, and MP designed the study. SH and MLH performed microdissection of MCL cells, IHC of LRPAP1, and interpretation of IHC. MK, ER, NF, LT, TB, MB, and NF performed the cloning and recombinat expression of the recombinant MCL–BCRs. NF performed the protein array experiments, proliferation, and cytotoxicity experiments. SJS provided MCL cells from peripheral blood and pleural effusions from patients. LT and MP are responsible for data analysis, interpretation of results, and writing of the manuscript.

Author information

Affiliations

  1. José Carreras Center for Immuno- and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany

    • Lorenz Thurner
    • , Natalie Fadle
    • , Maria Kemele
    • , Theresa Bock
    • , Moritz Bewarder
    • , Evi Regitz
    • , Frank Neumann
    • , Klaus-Dieter Preuss
    •  & Michael Pfreundschuh
  2. Dr. Senckenberg Institute of Pathology, Goethe University Hospital, Frankfurt am Main, Germany

    • Sylvia Hartmann
    •  & Martin-Leo Hansmann
  3. Institute of Medical Microbiology and Hygiene, Saarland University, Homburg/Saar, Germany

    • Anna Nimmesgern
    •  & Lutz von Müller
  4. Second Department of Medicine, University Hospital Schleswig-Holstein, Kiel, Germany

    • Christiane Pott
  5. Saarland University Medical School, Institute of Pathology, Homburg/Saar, Germany

    • Yoo-Jin Kim
    •  & Rainer Maria Bohle
  6. Lymphoma Program, Abramson Cancer Center University of Pennsylvania, Philadelphia, PA, USA

    • Mariusz Wasik
    •  & Stephen J. Schuster

Authors

  1. Search for Lorenz Thurner in:

  2. Search for Sylvia Hartmann in:

  3. Search for Natalie Fadle in:

  4. Search for Maria Kemele in:

  5. Search for Theresa Bock in:

  6. Search for Moritz Bewarder in:

  7. Search for Evi Regitz in:

  8. Search for Frank Neumann in:

  9. Search for Anna Nimmesgern in:

  10. Search for Lutz von Müller in:

  11. Search for Christiane Pott in:

  12. Search for Yoo-Jin Kim in:

  13. Search for Rainer Maria Bohle in:

  14. Search for Mariusz Wasik in:

  15. Search for Stephen J. Schuster in:

  16. Search for Martin-Leo Hansmann in:

  17. Search for Klaus-Dieter Preuss in:

  18. Search for Michael Pfreundschuh in:

Conflict of interest

University of Saarland applied for a relevant patent.

Corresponding author

Correspondence to Lorenz Thurner.

Electronic supplementary material

About this article

Publication history

Received

Revised

Accepted

Published

Issue Date

DOI

https://doi.org/10.1038/s41375-018-0182-1