161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS

• Published in: Blood advances Vol. 2; no. 12; pp. 1459 - 1469
• Main Authors: Sarhan, Dhifaf, Brandt, Ludwig, Felices, Martin, Guldevall, Karolin, Lenvik, Todd, Hinderlie, Peter, Curtsinger, Julie, Warlick, Erica, Spellman, Stephen R., Blazar, Bruce R., Weisdorf, Daniel J., Cooley, Sarah, Vallera, Daniel A., Önfelt, Björn, Miller, Jeffrey S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.06.2018; American Society of Hematology; Elsevier
• Subjects: Adult; Antibodies - therapeutic use; Drug Evaluation, Preclinical; GPI-Linked Proteins - immunology; HL-60 Cells; Humans; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Medicin och hälsovetenskap; Middle Aged; Myelodysplastic Syndromes - drug therapy; Myelodysplastic Syndromes - immunology; Myelodysplastic Syndromes - pathology; Myeloid Neoplasia; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - pathology; Receptors, IgG - immunology; Receptors, Immunologic - metabolism; Sialic Acid Binding Ig-like Lectin 3 - immunology; Tumor Cells, Cultured; Young Adult
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2017012369

Myelodysplastic syndrome (MDS) is a clonal heterogeneous stem cell disorder driven by multiple genetic and epigenetic alterations resulting in ineffective hematopoiesis. MDS has a high frequency of immune suppressors, including myeloid-derived suppressor cells (MDSCs), that collectively result in a poor immune response. MDSCs in MDS patients express CD155 that ligates the T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and delivers an inhibitory signal to natural killer (NK) cells. To mediate a productive immune response against MDS, negative regulatory checkpoints, like TIGIT, expressed on MDS NK cells must be overcome. NK cells can be directed to lyse MDS cells by bispecific killer engagers (BiKEs) that ligate CD16 on NK cells and CD33 on MDS cells. However, such CD16 × CD33 (1633) BiKEs do not induce the proliferative response in MDS NK cells needed to sustain their function. Here, we show that the addition of an NK stimulatory cytokine, interleukin-15 (IL-15), into the BiKE platform leads to productive IL-15 signaling without TIGIT upregulation on NK cells from MDS patients. Lower TIGIT expression allowed NK cells to resist MDSC inhibition. When compared with 1633 BiKE, 161533 trispecific killer engager (TriKE)–treated NK cells demonstrated superior killing kinetics associated with increased STAT5 phosphorylation. Furthermore, 161533 TriKE–treated MDS NK cells had higher proliferation and enhanced NK-cell function than 1633 BiKE–treated cells without the IL-15 linker. Collectively, our data demonstrate novel characteristics of the 161533 TriKE that support its application as an immunotherapeutic agent for MDS patients. •161533 TriKE–treated MDS NK cells proliferate and become activated to overcome tumor-induced NK cell dysfunction.•IL-15 induces the inhibitory checkpoint TIGIT on NK cells, but not when IL-15 is presented in the context of 161533 TriKE. [Display omitted]