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Preventing tumor escape by targeting a post-proteasomal trimming independent epitope

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Item Type:Article
Title:Preventing tumor escape by targeting a post-proteasomal trimming independent epitope
Creators Name:Textor, A. and Schmidt, K. and Kloetzel, P.M. and Weissbrich, B. and Perez, C. and Charo, J. and Anders, K. and Sidney, J. and Sette, A. and Schumacher, T.N.M. and Keller, C. and Busch, D.H. and Seifert, U. and Blankenstein, T.
Abstract:Adoptive T cell therapy (ATT) can achieve regression of large tumors in mice and humans; however, tumors frequently recur. High target peptide-major histocompatibility complex-I (pMHC) affinity and T cell receptor (TCR)-pMHC affinity are thought to be critical to preventing relapse. Here, we show that targeting two epitopes of the same antigen in the same cancer cells via monospecific T cells, which have similar pMHC and pMHC-TCR affinity, results in eradication of large, established tumors when targeting the apparently subdominant but not the dominant epitope. Only the escape but not the rejection epitope required postproteasomal trimming, which was regulated by IFN-gamma, allowing IFN-gamma-unresponsive cancer variants to evade. The data describe a novel immune escape mechanism and better define suitable target epitopes for ATT.
Keywords:Amino Acid Sequence, Antibody Affinity, Antigen T-Cell Receptors, Antigens, Histocompatibility Antigens Class I, Inbred C57BL Mice, Interferon-gamma, Leucyl Aminopeptidase, Neoplasms, Peptides, Proteasome Endopeptidase Complex, Signal Transduction, T-Lymphocyte Epitopes, T-Lymphocytes, Tumor Escape, Animals, Mice
Source:Journal of Experimental Medicine
ISSN:0022-1007
Publisher:Rockefeller University Press (U.S.A.)
Volume:213
Number:11
Page Range:2333-2348
Date:17 October 2016
Additional Information:Erratum in: J Exp Med 214(2): 567.
Official Publication:https://doi.org/10.1084/jem.20160636
PubMed:View item in PubMed

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