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PD-L1 siRNA-mediated silencing in acute myeloid leukemia enhances anti-leukemic T cell reactivity

Bone Marrow Transplantation volume 55, pages 2308–2318 (2020)Cite this article

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Abstract

Acute myeloid leukemia (AML) is an immune-susceptible malignancy, as demonstrated by its responsiveness to allogeneic stem cell transplantation (alloSCT). However, by employing inhibitory signaling pathways, including PD-1/PD-L1, leukemia cells suppress T cell-mediated immune attack. Notably, impressive clinical efficacy has been obtained with PD-1/PD-L1 blocking antibodies in cancer patients. Yet, these systemic treatments are often accompanied by severe toxicity, especially after alloSCT. Here, we investigated RNA interference technology as an alternative strategy to locally interfere with PD-1/PD-L1 signaling in AML. We demonstrated efficient siRNA-mediated PD-L1 silencing in HL-60 and patients’ AML cells. Importantly, WT1-antigen T cell receptor+ PD-1+ 2D3 cells showed increased activation toward PD-L1 silenced WT1+ AML. Moreover, PD-L1 silenced AML cells significantly enhanced the activation, degranulation, and IFN-γ production of minor histocompatibility antigen-specific CD8+ T cells. Notably, PD-L1 silencing was equally effective as PD-1 antibody blockade. Together, our study demonstrates that PD-L1 silencing may be an effective strategy to augment AML immune-susceptibility. This provides rationale for further development of targeted approaches to locally interfere with immune escape mechanisms in AML, thereby minimizing severe toxicity. In combination with alloSCT and/or adoptive T cell transfer, this strategy could be very appealing to boost graft-versus-leukemia immunity and improve outcome in AML patients.

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Fig. 1: siRNA-mediated silencing of PD-L1 on HL-60 cells.
Fig. 2: Effective siRNA-mediated silencing of PD-L1 in patient AML cells.
Fig. 3: Enhanced activation of WT1126–134 TCR expressing PD-1+ 2D3 cells by PD-L1 silenced AML cells.
Fig. 4: siRNA-mediated silencing of PD-L1 on AML cells improves cytotoxic T lymphocyte responses.

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Acknowledgements

This work was supported by grants from the Dutch Cancer Society (2012–5410), Dutch Cancer Society (2014–6716) and ZonMW (9125205).

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  1. These authors contributed equally: Diede van Ens, Charlotte M. Mousset, Tim J. A. Hutten

Authors and Affiliations

  1. Department of Laboratory Medicine - Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands

    Diede van Ens, Charlotte M. Mousset, Tim J. A. Hutten, Anniek B. van der Waart, Denise Vodegel, Hanny Fredrix, Rob Woestenenk, Loreto Parga-Vidal, Joop H. Jansen, Harry Dolstra & Willemijn Hobo

  2. Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute, Faculty of Medicine & Health Sciences, University of Antwerp, Antwerp, Belgium

    Diana Campillo-Davo, Sanne van der Heijden & Eva Lion

  3. Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands

    Nicolaas P. M. Schaap

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van Ens, D., Mousset, C.M., Hutten, T.J.A. et al. PD-L1 siRNA-mediated silencing in acute myeloid leukemia enhances anti-leukemic T cell reactivity. Bone Marrow Transplant 55, 2308–2318 (2020). https://doi.org/10.1038/s41409-020-0966-6

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