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J Exp Med. 2016 Oct 17;213(11):2333-2348. Epub 2016 Oct 3.

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

Author information

1
Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
2
Institute for Biochemistry, Charité, Campus Mitte, 10117 Berlin, Germany.
3
Berlin Institute of Health, 10117 Berlin, Germany.
4
Institute for Medical Microbiology, Immunology and Hygiene, Technical University, 81675 Munich, Germany.
5
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
6
The Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
7
Institute for Molecular and Clinical Immunology, Otto-von-Guericke-Universität, 39120 Magdeburg, Germany.
8
Friedrich Loeffler Institute of Medical Microbiology, University Medicine Greifswald, 17475 Greifswald, Germany.
9
Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany tblanke@mdc-berlin.de.
10
Institute of Immunology, Charité, Campus Buch, 13125 Berlin, Germany.

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-γ, allowing IFN-γ-unresponsive cancer variants to evade. The data describe a novel immune escape mechanism and better define suitable target epitopes for ATT.

PMID:
27697836
PMCID:
PMC5068242
DOI:
10.1084/jem.20160636
[Indexed for MEDLINE]
Free PMC Article

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