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Exploiting non-canonical translation to identify new targets for T cell-based cancer immunotherapy

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Abstract

Cryptic MHC I-associated peptides (MAPs) are produced via two mechanisms: translation of protein-coding genes in non-canonical reading frames and translation of allegedly non-coding sequences. In general, cryptic MAPs are coded by relatively short open reading frames whose translation can be regulated at the level of initiation, elongation or termination. In contrast to conventional MAPs, the processing of cryptic MAPs is frequently proteasome independent. The existence of cryptic MAPs derived from allegedly non-coding regions enlarges the scope of CD8 T cell immunosurveillance from a mere ~2% to as much as ~75% of the human genome. Considering that 99% of cancer-specific mutations are located in those allegedly non-coding regions, cryptic MAPs could furthermore represent a particularly rich source of tumor-specific antigens. However, extensive proteogenomic analyses will be required to determine the breath as well as the temporal and spatial plasticity of the cryptic MAP repertoire in normal and neoplastic cells.

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Abbreviations

AS:

Ankylosing spondylitis

B-LCL:

B-lymphoblastoid cell line

DRiP:

Defective ribosomal product

eIF:

Eukaryotic initiation factor

ER:

Endoplasmic reticulum

HLA:

Human leukocyte antigen

MAP:

MHC I-associated peptide

Met-tRNA Meti :

Methionine-loaded initiator tRNA

MHC I:

Major histocompatibility complex class I

MS:

Mass spectrometry

mTEC:

Medullary thymic epithelial cell

ORF:

Open reading frame

PRF:

Programmed ribosomal frameshifting

TAP:

Transporter associated with antigen processing

TSA:

Tumor-specific antigen

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Acknowledgements

Research performed in the authors’ lab was supported by a Grant from the Quebec Breast Cancer Foundation. C. M. L. is supported by a Cole Foundation fellowship. C. P. holds the Canadian Research Chair in Immunobiology. We apologize to authors whose work has not been cited due to space limitations.

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  1. Institute for Research in Immunology and Cancer, Université de Montréal, Station Centre-Ville, PO Box 6128, Montreal, QC, H3C 3J7, Canada

    Céline M. Laumont & Claude Perreault

  2. Department of Medicine, Faculty of Medicine, Université de Montréal, Station Centre-Ville, PO Box 6128, Montreal, QC, H3C 3J7, Canada

    Céline M. Laumont & Claude Perreault

  3. Division of Hematology, Hôpital Maisonneuve-Rosemont, 5415 de l’Assomption Boulevard, Montreal, QC, H1T 2M4, Canada

    Claude Perreault

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  1. Céline M. Laumont
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Laumont, C.M., Perreault, C. Exploiting non-canonical translation to identify new targets for T cell-based cancer immunotherapy. Cell. Mol. Life Sci. 75, 607–621 (2018). https://doi.org/10.1007/s00018-017-2628-4

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