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

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 associatedwith antigen processing( TAP). Administration of TAPsiRNA conjugated to a broad-range tumor-targeting nucleolin aptamerinhibited 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- TAPsiRNA 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 processingassociated protein, enhances anti-tumour immunity and the efficacy of immunotherapy.