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

Cancer Lett. 2019 Apr 10:447:164-173. doi: 10.1016/j.canlet.2019.01.016. Epub 2019 Jan 21.

Abstract

Tumor cells can escape immune surveillance through the programmed cell death protein 1 (PD-1) axis suppressing T cells. However, we recently demonstrated that high-affinity variants of soluble human programmed death-ligand 1 (shPD-L1) could diminish the suppression. We propose that in comparison to the wild-type shPD-L1, the further affinity enhancement will confer the molecule with opposite characteristics that augment T-cell activation and immunotherapeutic drug potential. In this study, a new shPD-L1 variant, L3C7c, has been generated to demonstrate ∼167 fold greater affinity than wild-type hPD-L1. The L3C7c-Fc fusion protein demonstrated completely opposite effects of conventional PD-1 axis by promoting redirected T-cell proliferation, activation and cytotoxicity in vitro, as being slightly better than that of anti-PD1-Ab (Pembrolizumab). Moreover, L3C7c-Fc was more effective than Pembrolizumab in enhancing redirected T cells' ability to suppress Mel624 melanoma growth in vivo. As a downsized L3C7c-Fc variant, L3C7v-Fc improved the anti-tumor efficacy in vivo when combined with dendritic cell vaccines. In conclusion, our studies demonstrate that high-affinity hPD-L1 variants could be developed as the next generation reagents for tumor immunotherapy based on the blockade of the PD-1 axis.

Keywords: Cancer; Immunotherapy; Protein engineering; T cells; hPD-L1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • B7-H1 Antigen / genetics*
  • B7-H1 Antigen / immunology*
  • Cancer Vaccines / immunology
  • Cell Line
  • Cell Line, Tumor
  • Female
  • Humans
  • Immunotherapy / methods
  • Lymphocyte Activation / immunology
  • Melanoma / immunology*
  • Melanoma / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, SCID
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • T-Lymphocytes / immunology*

Substances

  • Antibodies, Monoclonal, Humanized
  • B7-H1 Antigen
  • CD274 protein, human
  • Cancer Vaccines
  • Programmed Cell Death 1 Receptor
  • pembrolizumab