posted on 2024-03-13, 16:03authored byNoemi
A. Saavedra-Avila, Natalia B. Pigni, Donald R. Caldwell, Florencia Chena-Becerra, Jose Intano, Tony W. Ng, Divya Chennamadhavuni, Steven A. Porcelli, José A. Gascón, Amy R. Howell
Invariant natural killer T (iNKT) cells play an important
role
in many innate and adaptive immune responses, with potential applications
in cancer immunotherapy. The glycolipid KRN7000, an α-galactosylceramide,
potently activates iNKT cells but has shown limited anticancer effects
in human clinical trials conducted so far. In spite of almost three
decades of structure–activity relationship studies, no alternative
glycolipid has yet emerged as a superior clinical candidate. One reason
for the slow progress in this area is that standard mouse models do
not accurately reflect the specific ligand recognition by human iNKT
cells and their requirements for activation. Here we evaluated a series
of KRN7000 analogues using a recently developed humanized mouse model
that expresses a human αTCR chain sequence and human CD1d. In
this process, a more stimulatory, previously reported but largely
overlooked glycolipid was identified, and its activity was probed
and rationalized via molecular simulations.