Natural killer cells efficiently reject lymphoma silenced for the endoplasmic reticulum aminopeptidase associated with antigen processing.
The endoplasmic reticulum aminopeptidase ERAAP is involved in the final trimming of peptides for presentation by MHC class I (MHC-I) molecules. Herein, we show that ERAAP silencing results in MHC-I peptide-loading defects eliciting rejection of the murine T-cell lymphoma RMA in syngeneic mice. Although CD4 and CD8 T cells are also involved, rejection is mainly due to an immediate natural killer (NK) cell response and depends on the MHC-I-peptide repertoire because replacement of endogenous peptides with correctly trimmed, high-affinity peptides is sufficient to restore an NK-protective effect of MHC-I molecules through the Ly49C/I NK inhibitory receptors. At the crossroad between innate and adaptive immunity, ERAAP is therefore unique in its two-tiered ability to control tumor immunogenicity. Because a large fraction of human tumors express high levels of the homologous ERAP1 and/or ERAP2, the present findings highlight a convenient, novel target for cancer immunotherapy.
Oncohaematology Department, IRCCS, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
Loredana
L
Cifaldi
Elisa
E
Lo Monaco
Matteo
M
Forloni
Ezio
E
Giorda
Silvia
S
Lorenzi
Stefania
S
Petrini
Elisa
E
Tremante
Daniela
D
Pende
Franco
F
Locatelli
Patrizio
P
Giacomini
Doriana
D
Fruci
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D015153:Blotting, Western; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D015395:Histocompatibility Antigens Class I; D007694:Killer Cells, Natural / Q000276:immunology*; D007931:Leucyl Aminopeptidase / Q000235:genetics / Q000276:immunology*; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018613:Microscopy, Confocal
D015395:Histocompatibility Antigens Class I; D007931:Leucyl Aminopeptidase; C456799:puromycin-insensitive leucyl-specific aminopeptidase