Augmented anti-tumor activity of NK-92 cells expressing chimeric receptors of TGF-βR II and NKG2D

Abstract

The capacity of natural killer (NK) cells to kill tumor cells without specific antigen recognition provides an advantage over T cells and makes them potential effectors for tumor immunotherapy. However, the efficacy of NK cell adoptive therapy can be limited by the immunosuppressive tumor microenvironment. Transforming growth factor-β (TGF-β) is a potent immunosuppressive cytokine that can suppress NK cell function. To convert the suppressive signal induced by TGF-β to an activating signal, we genetically modified NK-92 cells to express a chimeric receptor with TGF-β type II receptor extracellular and transmembrane domains and the intracellular domain of NK cell-activating receptor NKG2D (TN chimeric receptor). NK-92 cells expressing TN receptors were resistant to TGF-β-induced suppressive signaling and did not down-regulate NKG2D. These modified NK-92 cells had higher killing capacity and interferon γ (IFN-γ) production against tumor cells compared with the control cells and their cytotoxicity could be further enhanced by TGF-β. More interestingly, the NK-92 cells expressing TN receptors were better chemo-attracted to the tumor cells expressing TGF-β. The presence of these modified NK-92 cells significantly inhibited the differentiation of human naïve CD4 T cells to regulatory T cells. NK-92-TN cells could also inhibit tumor growth in vivo in a hepatocellular carcinoma xenograft tumor model. Therefore, TN chimeric receptors can be a novel strategy to augment anti-tumor efficacy in NK cell adoptive therapy.

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…NCT02065362, NCT01955460, NCT00368082, NCT03089203). Additionally, NK92 cells transduced with a chimeric cytokine receptor in the form of extracellular domain of TGFβR2 fused to the signaling portion of NKG2D displayed better cytotoxic capacity [249]. Moreover, it is also possible to use chimeric cytokine receptor to modify T-cell behavior when exposed to certain cytokines.…”

Targeting Natural Killer Cells for Tumor Immunotherapy

“…Importantly, Galunisertib therapy could restore NKG2D and NKp30 expression on activated NK cells and enhanced NK cell cytotoxicity. Knockdown of TGFBR2 or SMAD3 in NK cells, engineering CB NK cells to express TGF-β dominant negative receptor II, or modifying NK cells using CAR containing TGF-β type II receptor extracellular and transmembrane domains, and the intracellular domain of NKG2D, are all under investigation and have shown great promise for the recovery of tumorsuppressed NK cell antitumor activity to treat patients with solid tumors (129)(130)(131).…”

NK-cells that identify glycopatterns and their anti-tumor potential against a background of epidemically significant viral infections

“…Lectin NK-populations variability occurs not only due to combinational co-expression of NKG2, KIR genes (killer Ig-like receptors), NKp genes (NCR or natural cytotoxic receptors) and CD genes on cells but also due to varying phenotypes of interacting molecules (including those which are part of di-and oligomeric homo-and hetero-structures similar to CD94NKG, or tetrameric HLA-E) and genetic RL variants (multi-allele ones belonging to NKG2C1/2/3 type; NKG2E phenotype as two alternative splicing forms NKG2E and NKG2H [27=24]). They gradually become apparent under post-genome changes when genetic chimeric products are constructed (shortened ones [belonging to NKG2Ce type -С-end shortened form -NKG2C3]; outer, transmembrane, and cytoplasmic / intracellular RL domains [belonging to NKG2F type that is expressed as an intracellular form only], products of genetic maps obtained for CD94-NKG2 contacts, and others) [12,27,39,40].…”

“…IL15 is a key interleukin here and crucial for NK-cells maturation, differentiation and survival; it potentiates cytotoxicity of NKG2-populations [6,24,30]. Suppression of NK-cells functions is influenced by transforming growth factor (TGF-beta1) of tumor nature [8,40]. CSF1 induces occurrence of RAE-1-delta on macrophages that infiltrate a tumor, and RAE-1-delta is a specific ligand that regulates NKG2D-populations [37].…”