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 van Hall, Eli Gilboa

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number3773
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

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transporter
immunity
peptides
Tumors
Immunity
tumors
Neoplasms
therapy
trypsinogen activation peptide
antigens
Small Interfering RNA
Cells
Therapeutics
mutations
peptide permease
antibodies
determinants
toxicity
lesions
Toxicity

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Tumor-targeted silencing of the peptide transporter TAP induces potent antitumor immunity. / Garrido, Greta; Schrand, Brett; Rabasa, Ailem; Levay, Agata; D’Eramo, Francesca; Berezhnoy, Alexey; Modi, Shrey; Gefen, Tal; Marijt, Koen; Doorduijn, Elien; Dudeja, Vikas; van Hall, Thorbald; Gilboa, Eli.

In: Nature communications, Vol. 10, No. 1, 3773, 01.12.2019.

Research output: Contribution to journalArticle

Garrido, G, Schrand, B, Rabasa, A, Levay, A, D’Eramo, F, Berezhnoy, A, Modi, S, Gefen, T, Marijt, K, Doorduijn, E, Dudeja, V, van Hall, T & Gilboa, E 2019, 'Tumor-targeted silencing of the peptide transporter TAP induces potent antitumor immunity', Nature communications, vol. 10, no. 1, 3773. https://doi.org/10.1038/s41467-019-11728-2
Garrido, Greta ; Schrand, Brett ; Rabasa, Ailem ; Levay, Agata ; D’Eramo, Francesca ; Berezhnoy, Alexey ; Modi, Shrey ; Gefen, Tal ; Marijt, Koen ; Doorduijn, Elien ; Dudeja, Vikas ; van Hall, Thorbald ; Gilboa, Eli. / Tumor-targeted silencing of the peptide transporter TAP induces potent antitumor immunity. In: Nature communications. 2019 ; Vol. 10, No. 1.
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