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Lymphoma

LRPAP1 is a frequent proliferation-inducing antigen of BCRs of mantle cell lymphomas and can be used for specific therapeutic targeting

Leukemia volume 33, pages 148–158 (2019)Cite this article

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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.

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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.

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Authors and 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

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  1. Lorenz Thurner
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Correspondence to Lorenz Thurner.

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University of Saarland applied for a relevant patent.

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In Memoriam of Professor Dr. Michael Pfreundschuh.

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Thurner, L., Hartmann, S., Fadle, N. et al. LRPAP1 is a frequent proliferation-inducing antigen of BCRs of mantle cell lymphomas and can be used for specific therapeutic targeting. Leukemia 33, 148–158 (2019). https://doi.org/10.1038/s41375-018-0182-1

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