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Immunotherapy

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

Leukemiavolume 33pages426438 (2019) | Download Citation

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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References

  1. 1.

    Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–87.

  2. 2.

    Knutson KL, Disis ML, Salazar LG. CD4 regulatory T cells in human cancer pathogenesis. Cancer Immunol Immunother. 2007;56:271–85.

  3. 3.

    Campbell JD, Cook G, Robertson SE, Fraser A, Boyd KS, Gracie JA, et al. Suppression of IL-2-induced T cell proliferation and phosphorylation of STAT3 and STAT5 by tumor-derived TGF beta is reversed by IL-15. J Immunol. 2001;167:553–61.

  4. 4.

    Glatman Zaretsky A, Konradt C, Depis F, Wing JB, Goenka R, Atria DG, et al. T regulatory cells support plasma cell populations in the bone marrow. Cell Rep. 2017;18:1906–16.

  5. 5.

    Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306.

  6. 6.

    Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017;27:109–18.

  7. 7.

    Nishikawa H, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Curr Opin Immunol. 2014;27:1–7.

  8. 8.

    Kiniwa Y, Miyahara Y, Wang HY, Peng W, Peng G, Wheeler TM, et al. CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res. 2007;13:6947–58.

  9. 9.

    Beyer M, Kochanek M, Giese T, Endl E, Weihrauch MR, Knolle PA, et al. In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma. Blood. 2006;107:3940–9.

  10. 10.

    Feyler S, von Lilienfeld-Toal M, Jarmin S, Marles L, Rawstron A, Ashcroft AJ, et al. CD4(+)CD25(+)FoxP3(+) regulatory T cells are increased whilst CD3(+)CD4(−)CD8(−)alphabetaTCR(+) double negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden. Br J Haematol. 2009;144:686–95.

  11. 11.

    Muthu Raja KR, Rihova L, Zahradova L, Klincova M, Penka M, Hajek R. Increased T regulatory cells are associated with adverse clinical features and predict progression in multiple myeloma. PLoS One. 2012;7:e47077.

  12. 12.

    Feng X, Zhang L, Acharya C, An G, Wen K, Qiu L, et al. Targeting CD38 suppresses induction and function of T regulatory cells to mitigate immunosuppression in multiple myeloma. Clin Cancer Res. 2017;23:4290–4300.

  13. 13.

    Marabelle A, Kohrt H, Sagiv-Barfi I, Ajami B, Axtell RC, Zhou G, et al. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest. 2013;123:2447–63.

  14. 14.

    Bulliard Y, Jolicoeur R, Zhang J, Dranoff G, Wilson NS, Brogdon JL. OX40 engagement depletes intratumoral Tregs via activating FcgammaRs, leading to antitumor efficacy. Immunol Cell Biol. 2014;92:475–80.

  15. 15.

    Paiva B, Mateos MV, Sanchez-Abarca LI, Puig N, Vidriales MB, Lopez-Corral L, et al. Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: a longitudinal analysis. Blood. 2016;127:1151–62.

  16. 16.

    Arce Vargas F, Furness AJS, Solomon I, Joshi K, Mekkaoui L, Lesko MH, et al. Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors. Immunity. 2017;46:577–86.

  17. 17.

    Giannopoulos K, Kaminska W, Hus I, Dmoszynska A. The frequency of T regulatory cells modulates the survival of multiple myeloma patients: detailed characterisation of immune status in multiple myeloma. Br J Cancer. 2012;106:546–52.

  18. 18.

    Muthu Raja KR, Kubiczkova L, Rihova L, Piskacek M, Vsianska P, Hezova R, et al. Functionally suppressive CD8 T regulatory cells are increased in patients with multiple myeloma: a cause for immune impairment. PLoS One. 2012;7:e49446.

  19. 19.

    Whiteside TL, Schuler P, Schilling B. Induced and natural regulatory T cells in human cancer. Expert Opin Biol Ther. 2012;12:1383–97.

  20. 20.

    Adeegbe DO, Nishikawa H. Natural and induced T regulatory cells in cancer. Front Immunol. 2013;4:190.

  21. 21.

    Frassanito MA, Ruggieri S, Desantis V, Di Marzo L, Leone P, Racanelli V, et al. Myeloma cells act as tolerogenic antigen-presenting cells and induce regulatory T cells in vitro. Eur J Haematol. 2015;95:65–74.

  22. 22.

    Feyler S, Scott GB, Parrish C, Jarmin S, Evans P, Short M, et al. Tumour cell generation of inducible regulatory T-cells in multiple myeloma is contact-dependent and antigen-presenting cell-independent. PLoS One. 2012;7:e35981.

  23. 23.

    Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128:384–94.

  24. 24.

    Tai YT, Anderson KC. A new era of immune therapy in multiple myeloma. Blood. 2016;128:318–9.

  25. 25.

    Tai YT, Anderson KC. Targeting CD38 alleviates tumor-induced immunosuppression. Oncotarget. 2017;8:112166–7.

  26. 26.

    Braga WM, da Silva BR, de Carvalho AC, Maekawa YH, Bortoluzzo AB, Rizzatti EG, et al. FOXP3 and CTLA4 overexpression in multiple myeloma bone marrow as a sign of accumulation of CD4(+) T regulatory cells. Cancer Immunol Immunother. 2014;63:1189–97.

  27. 27.

    Kawano Y, Zavidij O, Park J, Moschetta M, Kokubun K, Mouhieddine TH, et al. Blocking IFNRA1 inhibits multiple myeloma-driven Treg expansion and immunosuppression. J Clin Invest 2018;128: 2487–99.

  28. 28.

    Carpenter RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013;19:2048–60.

  29. 29.

    Tai YT, Mayes PA, Acharya C, Zhong MY, Cea M, Cagnetta A, et al. Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood. 2014;123:3128–38.

  30. 30.

    Tai YT, Anderson KC. Targeting B-cell maturation antigen in multiple myeloma. Immunotherapy. 2015;7:1187–99.

  31. 31.

    Ali SA, Shi V, Maric I, Wang M, Stroncek DF, Rose JJ, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood. 2016;128:1688–1700.

  32. 32.

    Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood. 2017;130:2594–602.

  33. 33.

    Tai YT, Acharya C, An G, Moschetta M, Zhong MY, Feng X, et al. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood. 2016;127:3225–36.

  34. 34.

    Matthes T, McKee T, Dunand-Sauthier I, Manfroi B, Park S, Passweg J, et al. Myelopoiesis dysregulation associated to sustained APRIL production in multiple myeloma-infiltrated bone marrow. Leukemia. 2015;29:1901–8.

  35. 35.

    Moreaux J, Cremer FW, Reme T, Raab M, Mahtouk K, Kaukel P, et al. The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature. Blood. 2005;106:1021–30.

  36. 36.

    Tucci M, Ciavarella S, Strippoli S, Brunetti O, Dammacco F, Silvestris F. Immature dendritic cells from patients with multiple myeloma are prone to osteoclast differentiation in vitro. Exp Hematol. 2011;39:773–83 e771.

  37. 37.

    Yaccoby S, Pennisi A, Li X, Dillon SR, Zhan F, Barlogie B, et al. Atacicept (TACI-Ig) inhibits growth of TACI(high) primary myeloma cells in SCID-hu mice and in coculture with osteoclasts. Leukemia. 2008;22:406–13.

  38. 38.

    Abe M, Kido S, Hiasa M, Nakano A, Oda A, Amou H, et al. BAFF and APRIL as osteoclast-derived survival factors for myeloma cells: a rationale for TACI-Fc treatment in patients with multiple myeloma. Leukemia. 2006;20:1313–5.

  39. 39.

    An G, Acharya C, Feng X, Wen K, Zhong M, Zhang L, et al. Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication. Blood. 2016;128:1590–603.

  40. 40.

    Marsters SA, Yan M, Pitti RM, Haas PE, Dixit VM, Ashkenazi A. Interaction of the TNF homologues BLyS and APRIL with the TNF receptor homologues BCMA and TACI. Curr Biol. 2000;10:785–8.

  41. 41.

    Tai YT, Li XF, Breitkreutz I, Song W, Neri P, Catley L, et al. Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment. Cancer Res. 2006;66:6675–82.

  42. 42.

    Yan M, Wang H, Chan B, Roose-Girma M, Erickson S, Baker T, et al. Activation and accumulation of B cells in TACI-deficient mice. Nat Immunol. 2001;2:638–43.

  43. 43.

    Castigli E, Wilson SA, Scott S, Dedeoglu F, Xu S, Lam KP, et al. TACI and BAFF-R mediate isotype switching in B cells. J Exp Med. 2005;201:35–39.

  44. 44.

    Sakurai D, Hase H, Kanno Y, Kojima H, Okumura K, Kobata T. TACI regulates IgA production by APRIL in collaboration with HSPG. Blood. 2007;109:2961–7.

  45. 45.

    Tsuji S, Cortesao C, Bram RJ, Platt JL, Cascalho M. TACI deficiency impairs sustained Blimp-1 expression in B cells decreasing long-lived plasma cells in the bone marrow. Blood. 2011;118:5832–9.

  46. 46.

    Garcia-Carmona Y, Cols M, Ting AT, Radigan L, Yuk FJ, Zhang L, et al. Differential induction of plasma cells by isoforms of human TACI. Blood. 2015;125:1749–58.

  47. 47.

    von Bulow GU, van Deursen JM, Bram RJ. Regulation of the T-independent humoral response by TACI. Immunity. 2001;14:573–82.

  48. 48.

    Castigli E, Scott S, Dedeoglu F, Bryce P, Jabara H, Bhan AK, et al. Impaired IgA class switching in APRIL-deficient mice. Proc Natl Acad Sci USA. 2004;101:3903–8.

  49. 49.

    Planelles L, Carvalho-Pinto CE, Hardenberg G, Smaniotto S, Savino W, Gomez-Caro R, et al. APRIL promotes B-1 cell-associated neoplasm. Cancer Cell. 2004;6:399–408.

  50. 50.

    Guadagnoli M, Kimberley FC, Phan U, Cameron K, Vink PM, Rodermond H, et al. Development and characterization of APRIL antagonistic monoclonal antibodies for treatment of B-cell lymphomas. Blood. 2011;117:6856–65.

  51. 51.

    Correale J, Villa A. Role of CD8+ CD25+ Foxp3+ regulatory T cells in multiple sclerosis. Ann Neurol. 2010;67:625–38.

  52. 52.

    Miyara M, Chader D, Sage E, Sugiyama D, Nishikawa H, Bouvry D, et al. Sialyl Lewis x (CD15s) identifies highly differentiated and most suppressive FOXP3 high regulatory T cells in humans. Proc Natl Acad Sci USA. 2015;112:7225–30.

  53. 53.

    Zhang L, Tai YT, Ho M, Xing L, Chauhan D, Gang A, et al. Regulatory B cell-myeloma cell interaction confers immunosuppression and promotes their survival in the bone marrow milieu. Blood Cancer J. 2017;7:e547.

  54. 54.

    Vieira PL, Christensen JR, Minaee S, O’Neill EJ, Barrat FJ, Boonstra A, et al. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol. 2004;172:5986–93.

  55. 55.

    Blair PA, Norena LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, et al. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity. 2010;32:129–40.

  56. 56.

    Mauri C, Menon M. Human regulatory B cells in health and disease: therapeutic potential. J Clin Invest. 2017;127:772–9.

  57. 57.

    Moreaux J, Legouffe E, Jourdan E, Quittet P, Reme T, Lugagne C, et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood. 2004;103:3148–57.

  58. 58.

    Wang G, Wang F, Ding W, Wang J, Jing R, Li H, et al. APRIL induces tumorigenesis and metastasis of colorectal cancer cells via activation of the PI3K/Akt pathway. PLoS One. 2013;8:e55298.

  59. 59.

    Hipp S, Tai YT, Blanset D, Deegen P, Wahl J, Thomas O, et al. A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo. Leukemia. 2017;31:1743–51.

  60. 60.

    Lee L, Draper B, Chaplin N, Philip B, Chin M, Galas-Filipowicz D, et al. An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma. Blood. 2018;131:746–58.

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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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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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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.

Corresponding authors

Correspondence to Yu-Tzu Tai or Kenneth C. Anderson.

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DOI

https://doi.org/10.1038/s41375-018-0242-6