IL-15 enhanced antibody-dependent cellular cytotoxicity mediated by NK cells and macrophages

Abstract

The goal of cancer immunotherapy is to stimulate the host immune system to attack malignant cells. Antibody-dependent cellular cytotoxicity (ADCC) is a pivotal mechanism of antitumor action of clinically employed antitumor antibodies. IL-15 administered to patients with metastatic malignancy by continuous i.v. infusion at 2 μg/kg/d for 10 days was associated with a 38-fold increase in the number and activation status of circulating natural killer (NK) cells and activation of macrophages which together are ADCC effectors. We investigated combination therapy of IL-15 with rituximab in a syngeneic mouse model of lymphoma transfected with human CD20 and with alemtuzumab (Campath-1H) in a xenograft model of human adult T cell leukemia (ATL). IL-15 greatly enhanced the therapeutic efficacy of both rituximab and alemtuzumab in tumor models. The additivity/synergy was shown to be associated with augmented ADCC. Both NK cells and macrophages were critical elements in the chain of interacting effectors involved in optimal therapeutic responses mediated by rituximab with IL-15. We provide evidence supporting the hypothesis that NK cells interact with macrophages to augment the NK-cell activation and expression of FcγRIV and the capacity of these cells to become effectors of ADCC. The present study supports clinical trials of IL-15 combined with tumor-directed monoclonal antibodies.

Intra-lineage Plasticity and Functional Reprogramming Maintain Natural Killer Cell Repertoire Diversity

“…IL-15 is a key homeostatic cytokine for NK cells and has been linked to vital processes including survival, differentiation, functionality and proliferation 14,15,17,[28][29][30] . However, it remains elusive how these processes come together at the population level to maintain stable and yet highly diversified subset repertoires within individuals.…”

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…NK cell count could therefore potentially serve as a prognostic biomarker for efficacy of anti-CD20 treatment. As additional means to augment NK-mediated anti-CD20 therapy (apart from glyco-optimization), combination with cytokines such as IL-15/21 was shown to increase the efficacy of anti-CD20 treatment (226)(227)(228). Lenalidomide, an immunomodulatory drug commonly used for multiple myeloma also enhances the effect of anti-CD20 administration on NK cell effector function, in part by promoting nanoscale reorganization of the cytoskeleton at the immunological synapse (229)(230)(231).…”

Interleukin-15 (dys)regulation of lymphoid homeostasis: Implications for therapy of autoimmunity and cancer

“…Their results provide evidence that NK cells play a role in the regulation of human tumors and highlight potential survival effects associated with increased NK cell activity. IL-15 preparations have been reported to be of value in combination with in vivo administered monoclonal antibodies (Moga et al, 2011;Wrangle et al, 2018;Zhang et al, 2018;Chen, X., et al 2015. 30th Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer.…”