Expanding earlier work on the novel repertoire of peptides presented by tumor cells deficient in the TAP transporter, Marijt et al. conducted a human proteome-wide search for membrane protein cytoplasmic tail- and signal peptide-derived peptides predicted to create epitopes to major class I HLAs, matching these with HLA peptidome data. They demonstrate that healthy humans possess naive, and some antigen-experienced, high-avidity T cells reactive to these epitopes. Such epitopes can provide novel shared vaccine or T cell targets with intrinsic tumor specificity due to presentation only in cells which have downregulated TAP transport.
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-I(low) 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.
Author Info: (1) Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands. (2) Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
Author Info: (1) Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands. (2) Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands. (3) Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands. (4) Department of Hematology, Leiden University Medical Center, Leiden, Netherlands. (5) Department of Immunology, Institute for Cell Biology, University of Tubingen, Tubingen, Germany. German Cancer Consortium, German Cancer Research Center, Tubingen, Germany. (6) Department of Immunology, Institute for Cell Biology, University of Tubingen, Tubingen, Germany. German Cancer Consortium, German Cancer Research Center, Tubingen, Germany. (7) Department of Immunology, Institute for Cell Biology, University of Tubingen, Tubingen, Germany. German Cancer Consortium, German Cancer Research Center, Tubingen, Germany. (8) Department of Hematology, Leiden University Medical Center, Leiden, Netherlands. (9) Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands. (10) Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands T.van_Hall@lumc.nl.
