Frontiers in Immunology (Aug 2019)

Sensitization of Tumors for Attack by Virus-Specific CD8+ T-Cells Through Antibody-Mediated Delivery of Immunogenic T-Cell Epitopes

  • Julian P. Sefrin,
  • Lars Hillringhaus,
  • Olaf Mundigl,
  • Karin Mann,
  • Doris Ziegler-Landesberger,
  • Heike Seul,
  • Gloria Tabares,
  • Dominic Knoblauch,
  • Andreas Leinenbach,
  • Irene Friligou,
  • Sebastian Dziadek,
  • Rienk Offringa,
  • Rienk Offringa,
  • Valeria Lifke,
  • Alexander Lifke

DOI
https://doi.org/10.3389/fimmu.2019.01962
Journal volume & issue
Vol. 10

Abstract

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Anti-tumor immunity is limited by a number of factors including the lack of fully activated T-cells, insufficient antigenic stimulation and the immune-suppressive tumor microenvironment. We addressed these hurdles by developing a novel class of immunoconjugates, Antibody-Targeted Pathogen-derived Peptides (ATPPs), which were designed to efficiently deliver viral T-cell epitopes to tumors with the aim of redirecting virus-specific memory T-cells against the tumor. ATPPs were generated through covalent binding of mature MHC class I peptides to antibodies specific for cell surface-expressed tumor antigens that mediate immunoconjugate internalization. By means of a cleavable linker, the peptides are released in the endosomal compartment, from which they are loaded into MHC class I without the need for further processing. Pulsing of tumor cells with ATPPs was found to sensitize these for recognition by virus-specific CD8+ T-cells with much greater efficiency than exogenous loading with free peptides. Systemic injection of ATPPs into tumor-bearing mice enhanced the recruitment of virus-specific T-cells into the tumor and, when combined with immune checkpoint blockade, suppressed tumor growth. Our data thereby demonstrate the potential of ATPPs as a means of kick-starting the immune response against “cold” tumors and increasing the efficacy of checkpoint inhibitors.

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