Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy.
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.
Reits
Eric A
EA
Division of Tumor Biology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
Hodge
James W
JW
Herberts
Carla A
CA
Groothuis
Tom A
TA
Chakraborty
Mala
M
Wansley
Elizabeth K
EK
Camphausen
Kevin
K
Luiten
Rosalie M
RM
de Ru
Arnold H
AH
Neijssen
Joost
J
Griekspoor
Alexander
A
Mesman
Elly
E
Verreck
Frank A
FA
Spits
Hergen
H
Schlom
Jeffrey
J
van Veelen
Peter
P
Neefjes
Jacques J
JJ
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology / Q000528:radiation effects*; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology / Q000528:radiation effects; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology; D014176:Protein Biosynthesis / Q000276:immunology / Q000528:radiation effects; D011494:Protein Kinases / Q000276:immunology; D011878:Radiotherapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D058570:TOR Serine-Threonine Kinases
D015789:HLA-A2 Antigen; D010455:Peptides; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases