ILT3.Fc-CD166 Interaction Induces Inactivation of p70 S6 Kinase and Inhibits Tumor Cell Growth.
Zheng XuChih-Chao ChangMuyang LiQing-Yin ZhangElena-Rodica M VasilescuVivette D'AgatiAristidis FloratosGeorge VladNicole Suciu-FocaPublished in: Journal of immunology (Baltimore, Md. : 1950) (2017)
The blockade of immune checkpoints by anti-receptor and/or anti-ligand mAb is one of the most promising approaches to cancer immunotherapy. The interaction between Ig-like transcript 3 (ILT3), a marker of tolerogenic dendritic cells, also known as LILRB4/LIR5/CD85k, and its still unidentified ligand on the surface of activated human T cells is potentially important for immune checkpoint blockade. To identify the ILT3 ligand, we generated mAb by immunizing mice with Jurkat acute T cell leukemia, which binds ILT3.Fc to its membrane. Flow cytometry, mass spectrometry, and Biacore studies demonstrated that the ILT3 ligand is a CD166/activated leukocyte cell adhesion molecule. Knockdown of CD166 in primary human T cells by nucleofection abolished the capacity of ILT3.Fc to inhibit CD4+ Th cell proliferation and to induce the generation of CD8+CD28- T suppressor cells. CD166 displays strong heterophilic interaction with CD6 and weaker homophilic CD166-CD166 cell adhesion interaction. ILT3.Fc inhibited the growth of CD166+ tumor cell lines (TCL) derived from lymphoid malignancies in vitro and in vivo. CRISPR-Cas9-based knockout of CD166 from TCL abrogated ILT3.Fc binding and its tumor-inhibitory effect. The mechanism underlying the effect of ILT3.Fc on tumor cell growth involves inhibition of the p70S6K signaling pathway. Blockade of CD166 by ILT3.Fc inhibited progression of human TCL in NOD.Cg-Prkdc Il-2rg/SzJ mice, suggesting its potential immunotherapeutic value.
Keyphrases
- dendritic cells
- endothelial cells
- cell proliferation
- signaling pathway
- crispr cas
- mass spectrometry
- cell adhesion
- induced apoptosis
- immune response
- flow cytometry
- metabolic syndrome
- adipose tissue
- bone marrow
- acute myeloid leukemia
- tyrosine kinase
- high resolution
- pi k akt
- hepatitis b virus
- skeletal muscle
- epithelial mesenchymal transition
- cell cycle
- genome editing
- high performance liquid chromatography
- pluripotent stem cells
- single cell
- simultaneous determination
- wild type
- protein kinase