The Journal of Experimental Medicine
Rockland Immunochemicals for Research
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Published online 24 April 2006 doi:10.1084/jem.20052494
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 5, 1259-1271
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ARTICLE

 Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy

Eric A. Reits1, James W. Hodge2, Carla A. Herberts1, Tom A. Groothuis1, Mala Chakraborty2, Elizabeth K.Wansley2, Kevin Camphausen3, Rosalie M. Luiten1, Arnold H. de Ru4, Joost Neijssen1, Alexander Griekspoor1, Elly Mesman1, Frank A. Verreck4, Hergen Spits1, Jeffrey Schlom2, Peter van Veelen4, and Jacques J. Neefjes1

1 Division of Tumor Biology and Division of Immunology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, Netherlands
2 Laboratory of Tumor Immunology and Biology, 3 Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
4 Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, and Centre for Medical Systems Biology, 2333 2A Leiden, Netherlands

CORRESPONDENCE Jacques Neefjes: j.neefjes{at}nki.nl

Radiotherapy is one of the most successful cancer therapies. Here the effect of irradiation on antigen presentation by MHC class I molecules was studied. Cell surface expression of MHC class I molecules was increased for many days in a radiation dose-dependent manner as a consequence of three responses. Initially, enhanced degradation of existing proteins occurred which resulted in an increased intracellular peptide pool. Subsequently, enhanced translation due to activation of the mammalian target of rapamycin pathway resulted in increased peptide production, antigen presentation, as well as cytotoxic T lymphocyte recognition of irradiated cells. In addition, novel proteins were made in response to {gamma}-irradiation, resulting in new peptides presented by MHC class I molecules, which were recognized by cytotoxic T cells. We show that immunotherapy is successful in eradicating a murine colon adenocarcinoma only when preceded by radiotherapy of the tumor tissue. Our findings indicate that directed radiotherapy can improve the efficacy of tumor immunotherapy.

Abbreviations used in this paper: EGFP, enhanced GFP; FRAP, fluorescence recovery after photobleaching; MS, mass spectrometry; mTOR, mammalian target of rapamycin; RDP, rapidly degraded proteins; rpHPLC, reverse phase HPLC; TAP, transporter associated with antigen processing.

J.W. Hodge and C.A. Herberts contributed equally to this work.

H. Spit's and E.A. Reits' present address is Division of Cell Biology and Histology, Academic Medical Center, 1105 AZ Amsterdam, Netherlands.


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