Tumor-targeted silencing of the peptide transporter TAP induces potent antitumor immunity

Greta Garrido, Brett Schrand, Ailem Rabasa, Agata Levay, Francesca D’Eramo, Alexey Berezhnoy, Shrey Modi, Tal Gefen, Koen Marijt, Elien Doorduijn, Vikas Dudeja, Thorbald Hall and Eli Gilboa ()
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Greta Garrido: University of Miami, Miller School of Medicine
Brett Schrand: University of Miami, Miller School of Medicine
Ailem Rabasa: University of Miami, Miller School of Medicine
Agata Levay: University of Miami, Miller School of Medicine
Francesca D’Eramo: University of Miami, Miller School of Medicine
Alexey Berezhnoy: University of Miami, Miller School of Medicine
Shrey Modi: University of Miami, Miller School of Medicine
Tal Gefen: University of Miami, Miller School of Medicine
Koen Marijt: Leiden University Medical Center
Elien Doorduijn: Leiden University Medical Center
Vikas Dudeja: University of Miami, Miller School of Medicine
Thorbald Hall: Leiden University Medical Center
Eli Gilboa: University of Miami, Miller School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Neoantigen burden is a major determinant of tumor immunogenicity, underscored by recent clinical experience with checkpoint blockade therapy. Yet the majority of patients do not express, or express too few, neoantigens, and hence are less responsive to immune therapy. Here we describe an approach whereby a common set of new antigens are induced in tumor cells in situ by transient downregulation of the transporter associated with antigen processing (TAP). Administration of TAP siRNA conjugated to a broad-range tumor-targeting nucleolin aptamer inhibited tumor growth in multiple tumor models without measurable toxicity, was comparatively effective to vaccination against prototypic mutation-generated neoantigens, potentiated the antitumor effect of PD-1 antibody or Flt3 ligand, and induced the presentation of a TAP-independent peptide in human tumor cells. Treatment with the chemically-synthesized nucleolin aptamer-TAP siRNA conjugate represents a broadly-applicable approach to increase the antigenicity of tumor lesions and thereby enhance the effectiveness of immune potentiating therapies.

Date: 2019
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DOI: 10.1038/s41467-019-11728-2

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