Activation of tumor-reactive CTL by weak agonists could be new design approach.(cytotoxic T lymphocytes)

2002 DEC 11 - (NewsRx.com & NewsRx.net) -- University of Texas, M.D. Anderson Cancer Center researchers have been working on a new angle in designing cancer vaccines.

A. Castilleja and colleagues explained: "To design side chain variants for modulation of immunogenicity, we modeled the complex of the HLA-A2 molecule with an immunodominant peptide, E75, from the HER-2/neu protooncogene protein recognized by CTL [cytotoxic T lymphocytes]."

"We identified the side chain orientation of E75. We modified E75 at the central Ser(5) (E75 wild-type), which points upward, by removing successively the HO (variant S5A) and the CH[subscript]2-OH (variant S5G)," the researchers said. "Replacement of the OH with an aminopropyl (CH[subscript]2)3-NH[subscript]3 (variant S5K) maintained a similar upward orientation of the side chain."

Castilleja and associates found that "S5A and S5G were stronger stimulators while S5K was a weaker stimulator than E75 for induction of lytic function, indicating that the OH group and its extension hindered TCR [T-cell receptor] activation.

"S5K-CTL survived longer than did CTL induced by E75 and the variants S5A and S5G, which became apoptotic after restimulation with the inducer. S5K-CTL also recognized E75 endogenously presented by the tumor by IFN [interferon]-gamma production and specific cytolysis. S5K-CTL expanded at stimulation with E75 or with E75 plus agonistic anti-Fas mAb. Compared with S5K-CTL that had been restimulated with the inducer S5K, ...