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

• Published in: Nature communications Vol. 10; no. 1; pp. 3773 - 13
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.08.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/89; 631/250/251/1567; 631/67/580; 64; 64/60; Animals; Antibodies; Anticancer properties; Antigen (tumor-associated); Antigen processing; Antigenicity; Antigens; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Antitumor activity; Aptamers; Aptamers, Nucleotide; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - immunology; Cancer Vaccines; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Down-Regulation; Epitopes - immunology; Female; FLT3L protein; Humanities and Social Sciences; Humans; Immune checkpoint; Immunity; Immunization; Immunogenicity; Immunogenicity, Vaccine; Immunotherapy; Lesions; Male; Membrane Proteins - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular Targeted Therapy; multidisciplinary; Mutation; Neoantigens; Neoplasms - immunology; Neoplasms - prevention & control; Neoplasms, Experimental; NIH 3T3 Cells; Nucleolin; Oligodeoxyribonucleotides; Organic chemistry; PD-1 protein; Peptide transporter; Peptides; Phosphoproteins; Programmed Cell Death 1 Receptor - immunology; RNA, Small Interfering - administration & dosage; RNA-Binding Proteins; Science; Science (multidisciplinary); siRNA; Spleen - immunology; Spleen - pathology; TAP protein; Therapy; Toxicity; Tumor cells; Tumors; Vaccination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11728-2

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. The anti-tumour immune response greatly depends on the number of tumour neoantigens. Here the authors show in mouse models that a therapeutic strategy aimed at increasing the number of neoantigens via downregulating TAP, an antigen processing associated protein, enhances anti-tumour immunity and the efficacy of immunotherapy.