Sensitization of Tumors for Attack by Virus-Specific CD8+ T-Cells Through Antibody-Mediated Delivery of Immunogenic T-Cell Epitopes.
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.
['Sefrin|Julian P|JP|', 'Hillringhaus|Lars|L|', 'Mundigl|Olaf|O|', 'Mann|Karin|K|', 'Ziegler-Landesberger|Doris|D|', 'Seul|Heike|H|', 'Tabares|Gloria|G|', 'Knoblauch|Dominic|D|', 'Leinenbach|Andreas|A|', 'Friligou|Irene|I|', 'Dziadek|Sebastian|S|', 'Offringa|Rienk|R|', 'Lifke|Valeria|V|', 'Lifke|Alexander|A|']
D000818:Animals D018414:CD8-Positive T-Lymphocytes D045744:Cell Line, Tumor D018984:Epitopes, T-Lymphocyte D005260:Female D004854:Herpesvirus 4, Human D006801:Humans D018796:Immunoconjugates D007167:Immunotherapy D051379:Mice D009369:Neoplasms D010455:Peptides
CD8+ T-cell immunogenicity antibody-targeted pathogen-derived peptides (ATPP) antigen-armed antibodies cancer immunotherapy immune tolerance targeted therapy