ERK5 knockdown generates mouse leukemia cells with low MHC class I levels that activate NK cells and block tumorigenesis.
Tumor cell-based vaccines are currently used in clinical trails, but they are in general poorly immunogenic because they are composed of cell extracts or apoptotic cells. Live tumor cells should be much better Ags provided that they are properly processed by the host immune system. We show herein that stable expression of a small hairpin RNA for ERK5 (shERK5) decreases ERK5 levels in human and mouse leukemic cells and leads to their elimination by NK cells in vivo. The shERK5 cells show down-regulation of MHC class I expression at the plasma membrane. Accordingly, ectopic activation of the ERK5 pathway induces MHC class I gene expression. Coinjection of shERK5-expressing cells into the peritoneum diminishes survival of engrafted wild-type tumor cells. Moreover, s.c. injection of shERK5-expressing cells strongly diminishes tumor development by wild-type cells. Our results show that shERK5 expression in leukemia cells effectively attenuates their tumor activity and allows their use as a tumor cell-based vaccine.
Charni
Seyma
S
Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5535, Université Montpellier 1 and 2, Montpellier, France;
Aguilo
Juan Ignacio
JI
Garaude
Johan
J
de Bettignies
Geoffroy
G
Jacquet
Chantal
C
Hipskind
Robert A
RA
Singer
Dinah
D
Anel
Alberto
A
Villalba
Martin
M
D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D055785:Gene Knockdown Techniques; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D007939:Leukemia L1210 / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D034741:RNA, Small Interfering / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D034741:RNA, Small Interfering; D048054:Mitogen-Activated Protein Kinase 7