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Targeting PD1–PDL1 immune checkpoint in plasmacytoid dendritic cell interactions with T cells, natural killer cells and multiple myeloma cells

Leukemia volume 29, pages 1441–1444 (2015)Cite this article

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Despite the advent of bortezomib, thalidomide and lenalidomide, relapse of multiple myeloma (MM) is common, and novel therapies are needed urgently.1 Interactions of MM cells with bone marrow (BM) accessory and immune effector cells inhibit antitumor immunity as well as induce MM growth, survival and drug resistance.1 For example, we showed that plasmacytoid dendritic cells (pDCs) are increased in the BM of MM patients compared with normal BM, and these contribute to immune dysfunction, as well as promote tumor cell growth and survival.2 Aberrant pDCs’ function in MM is evidenced by their interaction not only with MM cells but also with immune effector T cells: MM BM pDCs have decreased ability to trigger T-cell proliferation compared with normal pDCs.2 Dysfunctional T cells and natural killer (NK) cells in MM3,4 together with functionally defective pDCs2 confer immune suppression in MM. To date, the mechanism(s) and the role of immunoregulatory molecules mediating pDC–T cell and pDC–NK cell interactions in MM remain undefined. Here we extended our previous studies2, 5 to examine the role of immune checkpoint receptor programmed cell death protein 1 (PD1) and its ligand PDL1 in pDC–T cell and pDC–NK cell interactions in the MM BM milieu, and to determine whether this interaction represents a therapeutic target to restore antitumor immunity and cytotoxicity.

PD1 (CD279), a member of the CD28 family of receptors, is expressed on the surface of antigen-activated and -exhausted T cells.4 PD1 has two ligands, PDL1 (B7-H1; CD274) and PDL2 (B7-DC; CD273). Although PDL1 expression has not been observed in normal epithelial cells, it is highly expressed on many solid tumors.6 PDL2 is more broadly expressed on normal healthy tissues than PDL1. The physiological role of PD1 is to maintain T-cell homeostasis by restricting T-cell activation and proliferation, thereby preventing autoimmunity. Importantly, the interaction of PD1+ T cells with PDL1-expressing cells inhibits T-cell responses.7, 8, 9 In the context of MM, studies have demonstrated PD1-expressing T cells and NK cells in the MM BM milieu, as well as PDL1 on MM cells.3, 10, 11, 12, 13 However, the expression of PDL1–PD1 on MM patient-derived pDCs and its functional significance during pDC–MM–T–NK cell interactions remain undefined.

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References

  1. Anderson KC . The 39th David A. Karnofsky Lecture: bench-to-bedside translation of targeted therapies in multiple myeloma. J Clin Oncol 2012; 30: 445–452.

    Article  CAS  PubMed  Google Scholar 

  2. Chauhan D, Singh AV, Brahmandam M, Carrasco R, Bandi M, Hideshima T et al. Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target. Cancer Cell 2009; 16: 309–323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Benson Jr DM, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 2010; 116: 2286–2294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Atanackovic D, Luetkens T, Kroger N . Coinhibitory molecule PD-1 as a potential target for the immunotherapy of multiple myeloma. Leukemia 2014; 28: 993–1000.

    Article  CAS  PubMed  Google Scholar 

  5. Ray A, Tian Z, Das DS, Coffman RL, Richardson P, Chauhan D et al. A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib. Leukemia 2014; 28: 1716–1724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8: 793–800.

    Article  CAS  PubMed  Google Scholar 

  7. Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA . Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal 2012; 5: ra46.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 2014; 20: 5064–5074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mullard A . New checkpoint inhibitors ride the immunotherapy tsunami. Nat Rev Drug Discov 2013; 12: 489–492.

    Article  CAS  PubMed  Google Scholar 

  10. Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D et al. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-gamma and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood 2007; 110: 296–304.

    Article  CAS  PubMed  Google Scholar 

  11. Hallett WH, Jing W, Drobyski WR, Johnson BD . Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade. Biol Blood Marrow Transplant 2011; 17: 1133–1145.

    Article  CAS  PubMed  Google Scholar 

  12. Rosenblatt J, Avivi I, Vasir B, Uhl L, Munshi NC, Katz T et al. Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. Clin Cancer Res 2013; 19: 3640–3648.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tamura H, Ishibashi M, Yamashita T, Tanosaki S, Okuyama N, Kondo A et al. Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma. Leukemia 2013; 27: 464–472.

    Article  CAS  PubMed  Google Scholar 

  14. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ . Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007; 27: 111–122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kearl TJ, Jing W, Gershan JA, Johnson BD . Programmed death receptor-1/programmed death receptor ligand-1 blockade after transient lymphodepletion to treat myeloma. J Immunol 2013; 190: 5620–5628.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This investigation was supported by National Institutes of Health Specialized Programs of Research Excellence (SPORE) grant P50100707, PO1-CA078378 and RO1 CA050947. KCA is an American Cancer Society Clinical Research Professor.

Author Contributions

DC designed the research, analyzed the data and wrote the manuscript; AR performed the experiments, analyzed the data and wrote the manuscript; YS and DSD helped in flow cytometry; PR and NCM provided clinical samples; and KCA analyzed the data and wrote the manuscript.

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  1. D Chauhan and K C Anderson: Joint senior authorship.

Authors and Affiliations

  1. Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    A Ray, D S Das, Y Song, P Richardson, N C Munshi, D Chauhan & K C Anderson

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  1. A Ray
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  2. D S Das
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Correspondence to D Chauhan or K C Anderson.

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Ray, A., Das, D., Song, Y. et al. Targeting PD1–PDL1 immune checkpoint in plasmacytoid dendritic cell interactions with T cells, natural killer cells and multiple myeloma cells. Leukemia 29, 1441–1444 (2015). https://doi.org/10.1038/leu.2015.11

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