Artículo de revista
Amide-Linked C4″-saccharide modification of krn7000 provides potent stimulation of human invariant NKT cells and anti-tumor immunity in a humanized mouse model
Fecha
2020Registro en:
ACS Chem. Biol. 2020, 15, 3176−3186
10.1021/acschembio.0c00707
Autor
Saavedra Ávila, Noemí Alejandra
Keshipeddy, Santosh
Guberman-Pfeffer, Matthew J.
Pérez Gallegos, Ayax
Saini, Neeraj
Schafer, Carolina
Carreño, Leandro J.
Gascón, José A.
Porcelli, Steven A.
Howell, Amy R.
Institución
Resumen
Activation of invariant natural killer T (iNKT) cells
by α-galactosylceramides (α-GalCers) stimulates strong immune
responses and potent anti-tumor immunity. Numerous modifications
of the glycolipid structure have been assessed to derive
activating ligands for these T cells with altered and potentially
advantageous properties in the induction of immune responses.
Here, we synthesized variants of the prototypical α-GalCer,
KRN7000, with amide-linked phenyl alkane substitutions on the
C4″-position of the galactose ring. We show that these variants
have weak iNKT cell stimulating activity in mouse models but
substantially greater activity for human iNKT cells. The most
active of the C4″-amides in our study showed strong anti-tumor
effects in a partially humanized mouse model for iNKT cell responses. In silico analysis suggested that the tether length and degree of
flexibility of the amide substituent affected the recognition by iNKT cell antigen receptors of the C4″-amide substituted glycolipids
in complex with their antigen presenting molecule CD1d. Our findings establish the use of stable C4″-amide linked additions to the
sugar moiety for further exploration of the immunological effects of structural modifications of iNKT cell activating glycolipids and
highlight the critical need for more accurate animal models to assess these compounds for immunotherapeutic potential in humans.