Abstract 1524: CD137 (4-1BB) engagement fine-tunes the synergistic IL-15- and IL-21-driven NK cell proliferation

Abstract

To understand and dissect the mechanisms driving NK cell proliferation, we took advantage of the methodology used in cell therapy to numerically expand NK cells in the presence of K562-derived artificial Antigen Presenting Cells (aAPCs) and cytokines. For 9 consecutive weeks, high expression of CD137L by a K562-derived aAPC cell line was able to sustain NK cell expansion by 100 million-fold whereas low expression of CD137L by the parental K562 cell line supported the expansion by only 40,000-fold. The level of expression of CD137L, however, did not modulate the sensitivity of the K562 cell line to the intrinsic cytotoxicity of NK cells. Similarly, the low NK cell proliferation in the presence of the parental K562 cell line and cytokines was increased by adding agonistic anti-CD137 antibodies to levels similar to CD137L-expressing K562-derived aAPCs. Finally, the synergy between IL-15 and IL-21 was observed only upon CD137 engagement and the presence of aAPCs. Therefore, we conclude that NK cell proliferation requires cell-to-cell contact, the activation of CD137 axis, the presence of IL-15 (or its membranous form) and IL-21. By analogy with the three signals model required to activate T cells, we speculate, that the cell-to-cell contact represents “signal 1”, CD137 would be “signal 2” and cytokines would be “signal 3”. The precise nature of signal 1 remains to be defined. Citation Format: Laurent Vidard, Christine Dureuil-Sizaire, Jérémy Baudhuin, Lionel Vescovi, Laurence Durand, Véronique Sierra, Eric Parmantier. CD137 (4-1BB) engagement fine-tunes the synergistic IL-15- and IL-21-driven NK cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1524.