Introduction: The TNF superfamily (TNFSF) member OX40 (CD134) has been shown to enhance T cell function but its role on NK cells is poorly understood. CD137, another TNFSF member has been shown to enhance the anti-tumor activity of NK cells in various malignancies. This study examines the expression and function of OX40 on human and murine NK cells, and assesses its therapeutic efficacy as a target in murine B-cell lymphoma models.
Methods: In vitro flow cytometry-based assays using primary NK cells from healthy volunteers and syngeneic lymphoma mouse models were used.
Results: OX40 was transiently upregulated upon NK activation. In contrast to CD137, the induction of OX40 on human NK cells was dependent on cell-to-cell contact with either monocytes or T cells. Stimulation with agonistic anti-OX40 mAb, but not multimeric OX40 ligand, induced IFNγ and TNFα production by human NK cells, suggesting that the OX40 effects are dependent on antibody:FcγR mediated clustering. Whilst we observed increased human NK degranulation, there was no evidence of increased antibody-dependent cellular cytotoxicity (ADCC). In complementary murine studies, intravenous inoculation with BCL1 lymphoma into immunocompetent syngeneic mice resulted in transient upregulation of OX40 on murine NK cells. Combination treatment with anti-CD20 and anti-OX40 mAb produced a synergistic effect with more durable remissions.
Conclusion: The upregulation of OX40 on NK cells is more complex than CD137 and conditional upon interaction with other cell types. Anti-OX40 agonists may enhance NK-mediated anti-tumor activity in a cytokine-dependent manner instead of conventional ADCC, through antibody:FcγR-mediated receptor clustering.
Citation Format: Sean H. Lim, Anna H. Turaj, Jane Willoughby, Claude H.T. Chan, Christine A. Penfold, Peter W.M. Johnson, Martin J. Glennie, Mark S. Cragg, Ronald Levy. Augmentation of OX40-dependent NK mediated antitumor activity is dependent on antibody cross-linking [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B055.
- ©2016 American Association for Cancer Research.