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Harnessing PD-L1-specific cytotoxic T cells for anti-leukemia immunotherapy to defeat mechanisms of immune escape mediated by the PD-1 pathway

Leukemia volume 28, pages 236–238 (2014)Cite this article

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The T-cell receptor co-stimulatory pathways have important roles in regulating T-cell activation and tolerance. The B7-CD28 superfamily contains both co-stimulatory and inhibitory receptors, including CD28 and programmed cell death protein 1 (PD-1). In general, interactions between PD1 on T cells and the ligand PD-L1 (B7-H1) control the induction and maintenance of peripheral T-cell tolerance during normal immune responses.1 The interaction between PD1 and PD-L1 has been described to negatively regulate the proliferation and the cytokine production of T cells. The major role of the PD-1 pathway is not at the initial T-cell activation stage but rather to regulate effector T-cell responses in tissues by downregulating the activity of T cells in order to limit collateral tissue damage.2 However, in several types of leukemia as well as in multiple myeloma, the surface expression of PD-L1 on cancer cells inhibits cytotoxic lymphocytes due to elevated levels of PD1 on the surface of these T cells.3, 4, 5, 6, 7, 8 In this regard, PD-L1 is expressed on both malignant cells and infiltrating immune cells in a subset of aggressive B-cell lymphomas.9 Similarly, the upregulation of PD-L1 expression on myeloma cells has been described to induce T-cell apoptosis and anergy of tumor-specific T cells as well as enhancing aggressive myeloma-cell characteristics.7

Recently, we described that the immune system itself seems to have established a respective counteractive mechanism, that is, PD-L1-specific cytotoxic T-lymphocyte (CTL).10, 11 PD-L1-reactive CTLs can readily be isolated from peripheral blood of cancer patients and to a lesser extent from blood of healthy donors. These PD-L1-specific CTLs not only recognized and killed cancer cells, for example, cutaneous T-cell lymphoma cells, but also PD-L1-expressing antigen-presenting cells (APCs) in a PD-L1-dependent manner.

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References

  1. Dong H, Zhu G, Tamada K, Chen L . B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999; 5: 1365–1369.

    Article  CAS  PubMed  Google Scholar 

  2. Pardoll DM . The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252–264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Krejsgaard T, Odum N, Geisler C, Wasik MA, Woetmann A . Regulatory T cells and immunodeficiency in mycosis fungoides and Sezary syndrome. Leukemia 2012; 26: 424–432.

    Article  CAS  PubMed  Google Scholar 

  4. Kollgaard T, Petersen SL, Hadrup SR, Masmas TN, Seremet T, Andersen MH et al. Evidence for involvement of clonally expanded CD8+ T cells in anticancer immune responses in CLL patients following nonmyeloablative conditioning and hematopoietic cell transplantation. Leukemia 2005; 19: 2273–2280.

    Article  CAS  PubMed  Google Scholar 

  5. Ame-Thomas P, Le PJ, Yssel H, Caron G, Pangault C, Jean R et al. Characterization of intratumoral follicular helper T cells in follicular lymphoma: role in the survival of malignant B cells. Leukemia 2012; 26: 1053–1063.

    Article  CAS  PubMed  Google Scholar 

  6. van de Donk NW, Kamps S, Mutis T, Lokhorst HM . Monoclonal antibody-based therapy as a new treatment strategy in multiple myeloma. Leukemia 2012; 26: 199–213.

    Article  CAS  PubMed  Google Scholar 

  7. 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 

  8. Greaves P, Gribben JG . The role of B7 family molecules in hematologic malignancy. Blood 2013; 121: 734–744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MG, Xu ML et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res 2013; 19: 3462–3473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Munir S, Andersen GH, Met O, Donia M, Frosig TM, Larsen SK et al. HLA-restricted cytotoxic T cells that are specific for the immune checkpoint ligand PD-L1 occur with high frequency in cancer patients. Cancer Res 2013; 73: 1674–1776.

    Article  Google Scholar 

  11. Munir S, Andersen GH, Woetmann A, Odum N, Becker JC, Andersen MH . Cutaneous T cell lymphoma cells are targets for immune checkpoint ligand PD-L1-specific, cytotoxic T cells. Leukemia 2013; e-pub ahead of print 18 April 2013: doi:10.1038/leu.2013.118.

    Article  CAS  PubMed  Google Scholar 

  12. Hatta Y, Koeffler HP . Role of tumor suppressor genes in the development of adult T cell leukemia/lymphoma (ATLL). Leukemia 2002; 16: 1069–1085.

    Article  CAS  PubMed  Google Scholar 

  13. Kozako T, Yoshimitsu M, Fujiwara H, Masamoto I, Horai S, White Y et al. PD-1/PD-L1 expression in human T-cell leukemia virus type 1 carriers and adult T-cell leukemia/lymphoma patients. Leukemia 2009; 23: 375–382.

    Article  CAS  PubMed  Google Scholar 

  14. Mous R, Savage P, Remmerswaal EB, van Lier RA, Eldering E, van Oers MH . Redirection of CMV-specific CTL towards B-CLL via CD20-targeted HLA/CMV complexes. Leukemia 2006; 20: 1096–1102.

    Article  CAS  PubMed  Google Scholar 

  15. Peric Z, Cahu X, Chevallier P, Brissot E, Malard F, Guillaume T et al. Features of Epstein-Barr Virus (EBV) reactivation after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation. Leukemia 2011; 25: 932–938.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Merete Jonassen for excellent technical assistance and Per thor Straten for scientific discussions. This study was supported by Herlev Hospital, Danish Cancer Society and Danish Medical Research Council. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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  1. Department of Hematology and Oncology, Center for Cancer Immune Therapy (CCIT), Copenhagen University Hospital, Herlev, Denmark

    S M Ahmad, S K Larsen, I M Svane & M H Andersen

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  1. S M Ahmad
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Correspondence to M H Andersen.

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It should be noted, however, that Mads Hald Andersen has previously filed a patent application on the basis of the use of PD-L1 for vaccination. The rights of the patent application have been transferred to Copenhagen University Hospital, Herlev, through the Capital Region of Denmark.

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Ahmad, S., Larsen, S., Svane, I. et al. Harnessing PD-L1-specific cytotoxic T cells for anti-leukemia immunotherapy to defeat mechanisms of immune escape mediated by the PD-1 pathway. Leukemia 28, 236–238 (2014). https://doi.org/10.1038/leu.2013.261

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