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

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

Author information

1
Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands.
2
Department of Hematology, Leiden University Medical Center, Leiden, Netherlands.
3
Department of Immunology, Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
4
German Cancer Consortium, German Cancer Research Center, Tübingen, Germany.
5
Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands T.van_Hall@lumc.nl.

Abstract

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.

PMID:
30115740
PMCID:
PMC6122969
[Available on 2019-03-03]
DOI:
10.1084/jem.20180577

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