Identification of non-mutated neoantigens presented by TAP-deficient tumors

J Exp Med. 2018 Sep 3;215(9):2325-2337. doi: 10.1084/jem.20180577. Epub 2018 Aug 16.


Most T cell-based immunotherapies of cancer depend on intact antigen presentation by HLA class I molecules (HLA-I). However, defects in the antigen-processing machinery can cause downregulation of HLA-I, rendering tumor cells resistant to CD8+ T cells. Previously, we demonstrated that a unique category of cancer antigens is selectively presented by tumor cells deficient for the peptide transporter TAP, enabling a specific attack of such tumors without causing immunopathology in mouse models. With a novel combinatorial screening approach, we now identify 16 antigens of this category in humans. These HLA-A*02:01 presented peptides do not derive from the mutanome of cancers, but are of "self" origin and therefore constitute universal neoantigens. Indeed, CD8+ T cells specific for the leader peptide of the ubiquitously expressed LRPAP1 protein recognized TAP-deficient, HLA-Ilow lymphomas, melanomas, and renal and colon carcinomas, but not healthy counterparts. In contrast to personalized mutanome-targeted therapies, these conserved neoantigens and their cognate receptors can be exploited for immune-escaped cancers across diverse histological origins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / deficiency*
  • ATP-Binding Cassette Transporters / immunology
  • Antigen Presentation*
  • Antigens, Neoplasm / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Female
  • HLA-A2 Antigen / immunology*
  • Humans
  • LDL-Receptor Related Protein-Associated Protein / immunology*
  • Male
  • Neoplasm Proteins / immunology*
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Tumor Cells, Cultured
  • Tumor Escape*


  • ATP-Binding Cassette Transporters
  • Antigens, Neoplasm
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • LDL-Receptor Related Protein-Associated Protein
  • Neoplasm Proteins
  • transporter associated with antigen processing (TAP)

Associated data

  • SWISSPROT/P01591
  • SWISSPROT/P15289
  • SWISSPROT/O60613
  • SWISSPROT/P29459
  • SWISSPROT/P00739
  • SWISSPROT/P40259
  • SWISSPROT/P02743