ERK5 Knockdown Generates Mouse Leukemia Cells with Low MHC Class I Levels That Activate NK Cells and Block Tumorigenesis

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2009 Mar 7

PMID 19265117

Citations 17

Authors

Seyma Charni

Juan Ignacio Aguilo

Johan Garaude

Geoffroy de Bettignies

Chantal Jacquet

Robert A Hipskind

Dinah Singer

Alberto Anel

Martin Villalba

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

MAP kinase ERK5 modulates cancer cell sensitivity to extrinsic apoptosis induced by death-receptor agonists.

Espinosa-Gil S, Ivanova S, Alari-Pahissa E, Denizli M, Villafranca-Magdalena B, Vinas-Casas M Cell Death Dis. 2023; 14(11):715.

PMID: 37919293 PMC: 10622508. DOI: 10.1038/s41419-023-06229-6.

Clinical Significance and Regulation of ERK5 Expression and Function in Cancer.

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Proteomics of Melanoma Response to Immunotherapy Reveals Mitochondrial Dependence.

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Mutations in the Subunit of Mitochondrial Complex I Are Sufficient to Confer Increased Tumorigenic and Metastatic Potential to Cancer Cells.

Marco-Brualla J, Al-Wasaby S, Soler R, Romanos E, Conde B, Justo-Mendez R Cancers (Basel). 2019; 11(7).

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Impact of ERK5 on the Hallmarks of Cancer.

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References

Ruggeri L, Mancusi A, Burchielli E, Aversa F, Martelli M, Velardi A . Natural killer cell alloreactivity in allogeneic hematopoietic transplantation. Curr Opin Oncol. 2007; 19(2):142-7. DOI: 10.1097/CCO.0b013e3280148a1a. View

Bryceson Y, March M, Ljunggren H, Long E . Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood. 2005; 107(1):159-66. PMC: 1895346. DOI: 10.1182/blood-2005-04-1351. View

Kasai M, Yoneda T, Habu S, Maruyama Y, Okumura K, Tokunaga T . In vivo effect of anti-asialo GM1 antibody on natural killer activity. Nature. 1981; 291(5813):334-5. DOI: 10.1038/291334a0. View

Garaude J, Cherni S, Kaminski S, Delepine E, Chable-Bessia C, Benkirane M . ERK5 activates NF-kappaB in leukemic T cells and is essential for their growth in vivo. J Immunol. 2006; 177(11):7607-17. DOI: 10.4049/jimmunol.177.11.7607. View

Dzik W . Apoptosis, TGF beta and transfusion-related immunosuppression: Biologic versus clinical effects. Transfus Apher Sci. 2003; 29(2):127-9. DOI: 10.1016/S1473-0502(03)00115-0. View

Glas R, Franksson L, Une C, Eloranta M, Ohlen C, Orn A . Recruitment and activation of natural killer (NK) cells in vivo determined by the target cell phenotype. An adaptive component of NK cell-mediated responses. J Exp Med. 2000; 191(1):129-38. PMC: 2195802. DOI: 10.1084/jem.191.1.129. View

Aptsiauri N, Cabrera T, Garcia-Lora A, Lopez-Nevot M, Ruiz-Cabello F, Garrido F . MHC class I antigens and immune surveillance in transformed cells. Int Rev Cytol. 2007; 256:139-89. DOI: 10.1016/S0074-7696(07)56005-5. View

Akao Y, Nakagawa Y, Kitade Y, Kinoshita T, Naoe T . Downregulation of microRNAs-143 and -145 in B-cell malignancies. Cancer Sci. 2007; 98(12):1914-20. PMC: 11158757. DOI: 10.1111/j.1349-7006.2007.00618.x. View

Wodnar-Filipowicz A, Kalberer C . Function of natural killer cells in immune defence against human leukaemia. Swiss Med Wkly. 2006; 136(23-24):359-64. DOI: 10.4414/smw.2006.11360. View

10.

Lanier L . Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 2008; 9(5):495-502. PMC: 2669298. DOI: 10.1038/ni1581. View

11.

Imai K, Matsuyama S, Miyake S, Suga K, Nakachi K . Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet. 2000; 356(9244):1795-9. DOI: 10.1016/S0140-6736(00)03231-1. View

12.

Schowalter D, Tubb J, Liu M, Wilson C, Kay M . Heterologous expression of adenovirus E3-gp19K in an E1a-deleted adenovirus vector inhibits MHC I expression in vitro, but does not prolong transgene expression in vivo. Gene Ther. 1997; 4(4):351-60. DOI: 10.1038/sj.gt.3300398. View

13.

Carvajal-Vergara X, Tabera S, Montero J, Esparis-Ogando A, Lopez-Perez R, Mateo G . Multifunctional role of Erk5 in multiple myeloma. Blood. 2005; 105(11):4492-9. DOI: 10.1182/blood-2004-08-2985. View

14.

Pardo J, Balkow S, Anel A, Simon M . Granzymes are essential for natural killer cell-mediated and perf-facilitated tumor control. Eur J Immunol. 2002; 32(10):2881-7. DOI: 10.1002/1521-4141(2002010)32:10<2881::AID-IMMU2881>3.0.CO;2-K. View

15.

Diefenbach A, Jensen E, Jamieson A, Raulet D . Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature. 2001; 413(6852):165-71. PMC: 3900321. DOI: 10.1038/35093109. View

16.

Groh V, Wu J, Yee C, Spies T . Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature. 2002; 419(6908):734-8. DOI: 10.1038/nature01112. View

17.

Mullbacher A, Lobigs M, Hla R, Tran T, Stehle T, Simon M . Antigen-dependent release of IFN-gamma by cytotoxic T cells up-regulates Fas on target cells and facilitates exocytosis-independent specific target cell lysis. J Immunol. 2002; 169(1):145-50. DOI: 10.4049/jimmunol.169.1.145. View

18.

Hallett W, Murphy W . Positive and negative regulation of Natural Killer cells: therapeutic implications. Semin Cancer Biol. 2006; 16(5):367-82. DOI: 10.1016/j.semcancer.2006.07.003. View

19.

Berd D, MAGUIRE Jr H, McCue P, Mastrangelo M . Treatment of metastatic melanoma with an autologous tumor-cell vaccine: clinical and immunologic results in 64 patients. J Clin Oncol. 1990; 8(11):1858-67. DOI: 10.1200/JCO.1990.8.11.1858. View

20.

Terme M, Ullrich E, Delahaye N, Chaput N, Zitvogel L . Natural killer cell-directed therapies: moving from unexpected results to successful strategies. Nat Immunol. 2008; 9(5):486-94. DOI: 10.1038/ni1580. View