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Selective cytotoxic T-lymphocyte targeting of tumor immune escape variants

Abstract

Defects in major histocompatibility complex (MHC) class I–restricted antigen presentation are frequently observed in human cancers and result in escape of tumors from cytotoxic T lymphocyte (CTL) immune surveillance in mice. Here, we show the existence of a unique category of CTLs that can prevent this escape. The CTLs target an alternative repertoire of peptide epitopes that emerge in MHC class I at the surface of cells with impaired function of transporter associated with antigen processing (TAP), tapasin or the proteasome. These peptides, although derived from self antigens such as the commonly expressed Lass5 protein (also known as Trh4), are not presented by normal cells. This explains why they act as immunogenic neoantigens. The newly discovered epitopes can be exploited for immune intervention against processing-deficient tumors through adoptive T-cell transfer or peptide vaccination.

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Figure 1: RMA-S.B7-1–induced T cells selectively recognize and eradicate TAP-deficient cells.
Figure 2: Processing impairment at different stages results in presentation of TEIPPs on cells of diverse tissue origin.
Figure 3: TEIPP-specific CTL reactivity is MHC class I restricted.
Figure 4: Identification of a Db-presented TEIPP.
Figure 5: Analysis of Lass5 expression and vaccination with the Lass5-encoded peptide.

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Acknowledgements

The authors would like to thank G.J. Hämmerling for providing knockout mice and S. Stevanovic for supply of motif-bearing peptide libraries. This work was financially supported by the Dutch Cancer Society (UL2002-2709 to T.v.H. and S.L.), the Centre for Medical Systems Biology (a centre of excellence approved by the Netherlands Genomics Initiative), the Swedish Cancer Foundation, the Swedish Medical Research Council, the Royal Swedish Academy of Sciences and Accuro Immunology AB.

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Correspondence to Thorbald van Hall.

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Supplementary information

Supplementary Fig. 1

Kb- and Db-eluted peptides from TAP-deficient cells represent two different repertoires. (PDF 37 kb)

Supplementary Fig. 2

Mass spectrometry identification of three peptide sequences that are presented on TAP-deficient RMA-S cells. (PDF 208 kb)

Supplementary Fig. 3

The H-2Db-restricted TEIPP epitope is encoded by the Trh4 gene (PDF 116 kb)

Supplementary Fig. 4

Peptide MCLRMTAVM is detected in Db-eluted fractions from RMA-S. (PDF 220 kb)

Supplementary Table 1

Phenotypic characterization of TEIPP-specific CTL. (PDF 16 kb)

Supplementary Table 2

Identification of Kb-binding peptides from RMA-S. (PDF 11 kb)

Supplementary Table 3

Position screen in the mimotope peptide. (PDF 18 kb)

Supplementary Table 4

Determination of the Db peptide-epitope. (PDF 16 kb)

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van Hall, T., Wolpert, E., van Veelen, P. et al. Selective cytotoxic T-lymphocyte targeting of tumor immune escape variants. Nat Med 12, 417–424 (2006). https://doi.org/10.1038/nm1381

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