CD70 reverse signaling enhances NK cell function and immunosurveillance in CD27-expressing B-cell malignancies

Mohamad F. Al Sayed, Carla A. Ruckstuhl, Tamara Hilmenyuk, Christina Claus, Jean-Pierre Bourquin, Beat C. Bornhauser, Ramin Radpour, Carsten Riether and Adrian F. Ochsenbein

Key Points

  • CD27 expression on malignant B cells triggers CD70 reverse signaling in NK cells and improves lymphoma immunosurveillance.

  • CD70 reverse signaling in NK cells is mediated via the AKT signaling pathway and enhances survival and effector function.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.


The interaction of the tumor necrosis factor receptor (TNFR) CD27 with its ligand CD70 is an emerging target to treat cancer. CD27 signaling provides costimulatory signals to cytotoxic T cells but also increases the frequency of regulatory T cells. Similar to other TNFR ligands, CD70 has been shown to initiate intracellular signaling pathways (CD70 reverse signaling). CD27 is expressed on a majority of B-cell non–Hodgkin lymphoma, but its role in the immune control of lymphoma and leukemia is unknown. We therefore generated a cytoplasmic deletion mutant of CD27 (CD27-trunc) to study the role of CD70 reverse signaling in the immunosurveillance of B-cell malignancies in vivo. Expression of CD27-trunc on malignant cells increased the number of tumor-infiltrating interferon γ–producing natural killer (NK) cells. In contrast, the antitumoral T-cell response remained largely unchanged. CD70 reverse signaling in NK cells was mediated via the AKT signaling pathway and increased NK cell survival and effector function. The improved immune control by activated NK cells prolonged survival of CD27-trunc–expressing lymphoma-bearing mice. Finally, CD70 reverse signaling enhanced survival and effector function of human NK cells in a B-cell acute lymphoblastic leukemia xenotransplants model. Therefore, CD70 reverse signaling in NK cells contributes to the immune control of CD27-expressing B-cell lymphoma and leukemia.

  • Submitted December 11, 2016.
  • Accepted April 26, 2017.
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