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The Toll-like receptor 7/8 agonist resiquimod greatly increases the immunostimulatory capacity of human acute myeloid leukemia cells

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Abstract

Immunotherapy for leukemia is a promising targeted strategy to eradicate residual leukemic cells after standard therapy, in order to prevent relapse and to prolong the survival of leukemia patients. However, effective anti-leukemia immune responses are hampered by the weak immunogenicity of leukemic cells. Therefore, much effort is made to identify agents that could increase the immunogenicity of leukemic cells and activate the immune system. Synthetic agonists of Toll-like receptor (TLR)7 and TLR8 are already in use as anticancer treatment, because of their ability to activate several immune pathways simultaneously, resulting in effective antitumor immunity. However, for leukemic cells little is known about the expression of TLR7/8 and the direct effects of their agonists. We hypothesized that TLR7/8 agonist treatment of human acute myeloid leukemia (AML) cells would lead to an increased immunogenicity of AML cells. We observed expression of TLR7 and TLR8 in primary human AML cells and AML cell lines. Passive pulsing of primary AML cells with the TLR7/8 agonist R-848 resulted in increased expression of MHC molecules, production of proinflammatory cytokines, and enhanced allogeneic naïve T cell-stimulatory capacity. These effects were absent or suboptimal if R-848 was administered intracellularly by electroporation. Furthermore, when AML cells were cocultured with allogeneic PBMC in the presence of R-848, interferon (IFN)-γ was produced by allogeneic NK and NKT cells and AML cells were killed. In conclusion, the immunostimulatory effect of the TLR7/8 agonist R-848 on human AML cells could prove useful for the design of TLR-based immunotherapy for leukemia.

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Acknowledgments

This work was supported by Grant no. G.0370.08 and no. G.0082.08 of the Fund for Scientific Research, Flanders, Belgium (FWO-Vlaanderen), by research grants of the Foundation Against Cancer (Stichting tegen Kanker), by Grant no. 802 of the Antwerp University Concerted Research Action (BOF-GOA), by a Methusalem grant of the Antwerp University and by a part of the Interuniversity Attraction Poles (IAP) programme #P6/41 financed by the Belgian Government. Part of this research was kindly supported by the Antwerp University Hospital (UZA). E. L. J. M. Smits holds a fellowship of the Stichting Emmanuel van der Schueren of the Vlaamse Liga tegen Kanker (VLK). E. Lion was funded by a PhD grant of the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen).

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Authors and Affiliations

  1. Vaccine and Infectious Disease Institute (VIDI), Laboratory of Experimental Hematology, Faculty of Medicine, University of Antwerp, 2610, Antwerp, Belgium

    Evelien L. J. M. Smits, Nathalie Cools, Eva Lion, Kirsten Van Camp, Peter Ponsaerts, Zwi N. Berneman & Viggo F. I. Van Tendeloo

  2. Center for Cellular Therapy and Regenerative Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Antwerp, Belgium

    Zwi N. Berneman & Viggo F. I. Van Tendeloo

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  1. Evelien L. J. M. Smits
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  2. Nathalie Cools
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  3. Eva Lion
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  4. Kirsten Van Camp
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  5. Peter Ponsaerts
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  6. Zwi N. Berneman
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  7. Viggo F. I. Van Tendeloo
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Correspondence to Viggo F. I. Van Tendeloo.

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Smits, E.L.J.M., Cools, N., Lion, E. et al. The Toll-like receptor 7/8 agonist resiquimod greatly increases the immunostimulatory capacity of human acute myeloid leukemia cells. Cancer Immunol Immunother 59, 35–46 (2010). https://doi.org/10.1007/s00262-009-0721-8

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