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Targeting tumour cells with defects in the MHC Class I antigen processing pathway with CD8+ T cells specific for hydrophobic TAP- and Tapasin-independent peptides: the requirement for directed access into the ER

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Abstract

It is becoming increasingly apparent that the majority of tumours display defects in the MHC class I antigen processing pathway, particularly low levels of the transporters-associated with antigen processing (TAP) and tapasin. Thus, immunotherapy approaches targeting such tumours with CD8+ cytotoxic T lymphocytes (CTL) requires strategies to overcome these defects. Previously we had identified an antigen processing pathway by which cytosolically derived hydrophobic peptides could be presented in the absence of TAP. Here we show in the tapasin-negative cell line 721.220 that a number of these hydrophobic TAP-independent peptides can also be presented in a tapasin-independent manner. Yet when these experiments were extended to tumour cell lines derived from small cell lung cancer (SCLC), which we show to be tapasin deficient in addition to TAP-negative, the TAP-, tapasin-independent peptides were not presented. This lack of presentation could be rectified by pre-treatment of SCLC cells with IFNγ. Alternatively, by directing the TAP-, tapasin-independent peptides into the endoplasmic reticulum (ER) via an ER signal sequence, these peptides were presented efficiently by SCLC cells. We infer from this data that the TAP-independent pathway for presentation of hydrophobic peptides generates a low concentration of peptide in the ER and, for tumour cells which also lack tapasin, this concentration of antigenic peptide is insufficient to load onto MHC class I molecules. Thus, for immunotherapeutic approaches to target SCLC and other tumours with defects in the MHC class I antigen processing pathway it will be important to consider strategies that address tapasin-defects.

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Abbreviations

ER:

Endoplasmic reticulum

EBV:

Epstein-Barr virus

CTL:

Cytotoxic T lymphocyte

PLC:

Peptide loading complex

SCLC:

Small cell lung cancer

TAP:

Transporters associated with antigen processing

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Acknowledgments

This work was supported by grants from North West Cancer Research Fund and Cancer Research UK. We thank the Department of Immunology (RLBUHT, Liverpool, UK) for HLA typing, and Drs A. Hislop (Birmingham, UK), T. Elliott (Southampton, UK) and P. Lehner (Cambridge, UK) for providing valuable reagents.

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Authors and Affiliations

  1. Division of Medical Microbiology, University of Liverpool, 8th Floor Duncan Building, Daulby Street, L69 3GA, Liverpool, UK

    Farah Aladin, Elizabeth Humphries & Neil Blake

  2. School of Biomedical Sciences, University of Liverpool, Liverpool, UK

    Farah Aladin & Judy Coulson

  3. CRUK Institute for Cancer Studies, University of Birmingham, Birmingham, UK

    Georg Lautscham

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  1. Farah Aladin
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  2. Georg Lautscham
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  3. Elizabeth Humphries
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  4. Judy Coulson
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  5. Neil Blake
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Correspondence to Neil Blake.

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Aladin, F., Lautscham, G., Humphries, E. et al. Targeting tumour cells with defects in the MHC Class I antigen processing pathway with CD8+ T cells specific for hydrophobic TAP- and Tapasin-independent peptides: the requirement for directed access into the ER. Cancer Immunol Immunother 56, 1143–1152 (2007). https://doi.org/10.1007/s00262-006-0263-2

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  • DOI: https://doi.org/10.1007/s00262-006-0263-2

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