Identification of non-mutated neoantigens presented by TAP-deficient tumors
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.
Source: The Journal of Experimental Medicine - Category: Internal Medicine Authors: Marijt, K. A., Blijleven, L., Verdegaal, E. M. E., Kester, M. G., Kowalewski, D. J., Rammensee, H.-G., Stevanovic, S., Heemskerk, M. H. M., van der Burg, S. H., van Hall, T. Tags: Tumor Immunology Articles Source Type: research
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