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Immunotherapy

APRIL signaling via TACI mediates immunosuppression by T regulatory cells in multiple myeloma: therapeutic implications

Leukemia volume 33, pages 426–438 (2019)Cite this article

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Abstract

We investigate here how APRIL impacts immune regulatory T cells and directly contributes to the immunosuppressive multiple myeloma (MM) bone marrow (BM) microenvironment. First, APRIL receptor TACI expression is significantly higher in regulatory T cells (Tregs) than conventional T cells (Tcons) from the same patient, confirmed by upregulated Treg markers, i.e., Foxp3, CTLA-4. APRIL significantly stimulates proliferation and survival of Tregs, whereas neutralizing anti-APRIL monoclonal antibodies (mAbs) inhibit these effects. Besides TACI-dependent induction of cell cycle progression and anti-apoptosis genes, APRIL specifically augments Foxp3, IL-10, TGFβ1, and PD-L1 in Tregs to further enhance Treg-inhibited Tcon proliferation. APRIL further increases MM cell-driven Treg (iTreg) via TACI-dependent proliferation associated with upregulated IL-10, TGFβ1, and CD15s in iTreg, which further inhibits Tcons. Osteoclasts producing APRIL and PD-L1 significantly block Tcon expansion by iTreg generation, which is overcome by combined treatment with anti-APRIL and anti-PD1/PD-L1 mAbs. Finally, APRIL increases IL-10-producing B regulatory cells (Bregs) via TACI on BM Bregs of MM patients. Taken together, these results define novel APRIL actions via TACI on Tregs and Bregs to promote MM cell survival, providing the rationale for targeting APRIL/TACI system to alleviate the immunosuppressive BM milieu and improve patient outcome in MM.

Key points

  • APRIL signaling via TACI on Tregs and Breg contributes to the immunosuppressive MM BM milieu.

  • Besides MM cells, therapeutic anti-APRIL mAbs may further affect Treg and Breg, thereby attenuating myeloma-induced and OC-induced immunosuppression.

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Acknowledgements

We thank Drs. G. An, L. Zhang, X. Y. Feng, Y. Xu, and Professor  L. Qiu during the early phase of this study. The authors also thank clinical research coordinators of the LeBow Institute for Myeloma Therapeutics and the Jerome Lipper Multiple Myeloma Center of the Dana-Farber Cancer Institute for support and help.

Funding

This work was supported in part by grants from the National Institutes of Health Grants RO1-124929 to Dr. Nikhil C. Munshi; P50-100007, and PO1-155258 to Drs. Kenneth C. Anderson and Nikhil C. Munshi, and RO1-50947 to Dr. Kenneth C. Anderson. Dr. Kenneth C. Anderson is an American Cancer Society Clinical Research Professor.

Author contributions

Conception and design: Y.-T. Tai, K.C. Anderson; Development of methodology: L. Lin, L.J. Xing, T. Yu, C. Acharya, and Y.-T. Tai; Acquisition of data (provided reagents, facilities, etc.): L. Lin, L.J. Xing, S.-F. Cho, T. Yu, K. Wen, P. A. Hsieh, and C. Acharya; Reagents and materials: J. Dulos and A.v. Elsas; Analysis and interpretation of data (statistical analysis, biostatistics analysis): L. Lin, L.J. Xing, S.-F. Cho, T. Yu, and Y.-T. Tai; Provided acquired and managed patients: N.  Munshi, P. Richardson, and K.C. Anderson; Writing, review, and/or revision of the manuscript: Y.-T. Tai, J. Dulos, A.v. Elsas, and K.C. Anderson; Study supervision: Y.-T. Tai and K.C. Anderson.

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Authors and Affiliations

  1. Jerome Lipper Multiple Myeloma Center, LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Yu-Tzu Tai, Liang Lin, Lijie Xing, Shih-Feng Cho, Tengteng Yu, Kenneth Wen, Phillip A. Hsieh, Nikhil Munshi, Paul Richardson & Kenneth C. Anderson

  2. Department of Hematology, Shandong Provincial Hospital affiliated to Shandong University, No. 324, Jingwu Road, Jinan, Shandong, 250021, People’s Republic of China

    Lijie Xing

  3. Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    Shih-Feng Cho

  4. Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Shih-Feng Cho

  5. Department of Internal Medicine, University of Mississippi Medical Center, Jackson, MS, USA

    Chirag Acharya

  6. Aduro Biotech Europe, Oss, The Netherlands

    John Dulos & Andrea van Elsas

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  1. Yu-Tzu Tai
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  11. Nikhil Munshi
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Correspondence to Yu-Tzu Tai or Kenneth C. Anderson.

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Conflict of interest

N.C.M. serves on advisory boards to Millennium, Celgene, and Novartis. K.C.A. serves on advisory boards Celgene, Millennium and Gilead Sciences and is a Scientific founder of OncoPep and C4 Therapeutics. P.R. is on advisory board of Celgene, Millennium and Johnson & Johnson. J.D. and A.v.E. are employees of Aduro Biotech Europe. The remaining authors declare that they have no conflict of interest.

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Tai, YT., Lin, L., Xing, L. et al. APRIL signaling via TACI mediates immunosuppression by T regulatory cells in multiple myeloma: therapeutic implications. Leukemia 33, 426–438 (2019). https://doi.org/10.1038/s41375-018-0242-6

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