High-affinity human programmed death-1 ligand-1 variant promotes redirected T cells to kill tumor cells

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Tumor cells evade immune surveillance by suppressing T cells via the programmed cell death protein 1 (PD-1) pathway.
• Previous research indicated that high-affinity soluble human programmed death-ligand 1 (shPD-L1) variants could reduce this suppression.

Purpose of the Study:

• To investigate if further enhancing the affinity of shPD-L1 variants could reverse PD-1 axis suppression and augment T-cell activation for immunotherapy.
• To evaluate the therapeutic potential of a novel high-affinity shPD-L1 variant, L3C7c.

Main Methods:

• Generation of a new shPD-L1 variant (L3C7c) with significantly increased affinity compared to wild-type hPD-L1.
• Assessment of L3C7c-Fc fusion protein's effects on T-cell proliferation, activation, and cytotoxicity in vitro.
• In vivo studies comparing L3C7c-Fc and Pembrolizumab in suppressing melanoma growth.
• Evaluation of a downsized L3C7v-Fc variant combined with dendritic cell vaccines.

Main Results:

• The L3C7c variant demonstrated approximately 167-fold greater affinity than wild-type hPD-L1.
• L3C7c-Fc promoted T-cell proliferation, activation, and cytotoxicity in vitro, exhibiting effects opposite to the conventional PD-1 axis.
• L3C7c-Fc outperformed Pembrolizumab in enhancing T-cell-mediated suppression of melanoma growth in vivo.
• A downsized L3C7v-Fc variant improved anti-tumor efficacy when used with dendritic cell vaccines.

Conclusions:

• High-affinity shPD-L1 variants can be engineered to possess reversed functionality, promoting T-cell activation instead of suppression.
• These engineered shPD-L1 variants represent a promising next generation of reagents for tumor immunotherapy by effectively blocking the PD-1 axis.