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Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAFV600E Melanoma Lines with Vemurafenib.
Cancer Immunol Res. 2017 07; 5(7):582-593.CI

Abstract

Over 60% of human melanoma tumors bear a mutation in the BRAF gene. The most frequent mutation is a substitution at codon 600 (V600E), leading to a constitutively active BRAF and overactivation of the MAPK pathway. Patients harboring mutated BRAF respond to kinase inhibitors such as vemurafenib. However, these responses are transient, and relapses are frequent. Melanoma cells are efficiently lysed by activated natural killer (NK) cells. Melanoma cells express several stress-induced ligands that are recognized by activating NK-cell receptors. We have investigated the effect of vemurafenib on the immunogenicity of seven BRAF-mutated melanoma cells to NK cells and on their growth and sensitivity to NK-cell-mediated lysis. We showed that vemurafenib treatment modulated expression of ligands for two activating NK receptors, increasing expression of B7-H6, a ligand for NKp30, and decreasing expression of MICA and ULBP2, ligands for NKG2D. Vemurafenib also increased expression of HLA class I and HLA-E molecules, likely leading to higher engagement of inhibitory receptors (KIRs and NKG2A, respectively), and decreased lysis of vemurafenib-treated melanoma cell lines by cytokine-activated NK cells. Finally, we showed that whereas batimastat (a broad-spectrum matrix metalloprotease inhibitor) increased cell surface ULBP2 by reducing its shedding, vemurafenib lowered soluble ULBP2, indicating that BRAF signal inhibition diminished expression of both cell-surface and soluble forms of NKG2D ligands. Vemurafenib, inhibiting BRAF signaling, shifted the balance of activatory and inhibitory NK ligands on melanoma cells and displayed immunoregulatory effects on NK-cell functional activities. Cancer Immunol Res; 5(7); 582-93. ©2017 AACR.

Authors+Show Affiliations

INSERM UMRS1160, Institut Universitaire d'Hématologie, Paris, France.INSERM UMRS1160, Institut Universitaire d'Hématologie, Paris, France.INSERM UMRS1160, Institut Universitaire d'Hématologie, Paris, France.INSERM UMRS1160, Institut Universitaire d'Hématologie, Paris, France.INSERM-CIC Institut Gustave Roussy, Villejuif, France.INSERM-CIC Institut Gustave Roussy, Villejuif, France.Aix Marseille Université, CNRS, INSERM, CIML, Marseille, France. Assistance Publique-Hôpitaux de Marseille, Hôpital de la Conception, Service d'Immunologie, Marseille, France.Aix Marseille Université, CNRS, INSERM, CIML, Marseille, France. Assistance Publique-Hôpitaux de Marseille, Hôpital de la Conception, Service d'Immunologie, Marseille, France.INSERM U932, Institut Curie, Paris, France.UMR 892-CRCNA, Institut de Recherche Thérapeutique de l'Université de Nantes, Nantes, France.UMR 892-CRCNA, Institut de Recherche Thérapeutique de l'Université de Nantes, Nantes, France.Institut Roche, Boulogne-Billancourt, France.Institut Roche, Boulogne-Billancourt, France.Service de Biochimie et Génétique Moléculaire, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.INSERM UMRS1160, Institut Universitaire d'Hématologie, Paris, France.Dermatology department, Hôpital Cochin, Paris, France.INSERM UMRS1160, Institut Universitaire d'Hématologie, Paris, France. anne.caignard@inserm.fr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28576831

Citation

Frazao, Alexandra, et al. "Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands On BRAFV600E Melanoma Lines With Vemurafenib." Cancer Immunology Research, vol. 5, no. 7, 2017, pp. 582-593.
Frazao A, Colombo M, Fourmentraux-Neves E, et al. Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAFV600E Melanoma Lines with Vemurafenib. Cancer Immunol Res. 2017;5(7):582-593.
Frazao, A., Colombo, M., Fourmentraux-Neves, E., Messaoudene, M., Rusakiewicz, S., Zitvogel, L., Vivier, E., Vély, F., Faure, F., Dréno, B., Benlalam, H., Bouquet, F., Savina, A., Pasmant, E., Toubert, A., Avril, M. F., & Caignard, A. (2017). Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAFV600E Melanoma Lines with Vemurafenib. Cancer Immunology Research, 5(7), 582-593. https://doi.org/10.1158/2326-6066.CIR-16-0380
Frazao A, et al. Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands On BRAFV600E Melanoma Lines With Vemurafenib. Cancer Immunol Res. 2017;5(7):582-593. PubMed PMID: 28576831.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAFV600E Melanoma Lines with Vemurafenib. AU - Frazao,Alexandra, AU - Colombo,Marina, AU - Fourmentraux-Neves,Emmanuelle, AU - Messaoudene,Meriem, AU - Rusakiewicz,Sylvie, AU - Zitvogel,Laurence, AU - Vivier,Eric, AU - Vély,Frédéric, AU - Faure,Florence, AU - Dréno,Brigitte, AU - Benlalam,Houssem, AU - Bouquet,Fanny, AU - Savina,Ariel, AU - Pasmant,Eric, AU - Toubert,Antoine, AU - Avril,Marie-Françoise, AU - Caignard,Anne, Y1 - 2017/06/02/ PY - 2016/12/21/received PY - 2017/04/10/revised PY - 2017/05/25/accepted PY - 2017/6/4/pubmed PY - 2018/4/3/medline PY - 2017/6/4/entrez SP - 582 EP - 593 JF - Cancer immunology research JO - Cancer Immunol Res VL - 5 IS - 7 N2 - Over 60% of human melanoma tumors bear a mutation in the BRAF gene. The most frequent mutation is a substitution at codon 600 (V600E), leading to a constitutively active BRAF and overactivation of the MAPK pathway. Patients harboring mutated BRAF respond to kinase inhibitors such as vemurafenib. However, these responses are transient, and relapses are frequent. Melanoma cells are efficiently lysed by activated natural killer (NK) cells. Melanoma cells express several stress-induced ligands that are recognized by activating NK-cell receptors. We have investigated the effect of vemurafenib on the immunogenicity of seven BRAF-mutated melanoma cells to NK cells and on their growth and sensitivity to NK-cell-mediated lysis. We showed that vemurafenib treatment modulated expression of ligands for two activating NK receptors, increasing expression of B7-H6, a ligand for NKp30, and decreasing expression of MICA and ULBP2, ligands for NKG2D. Vemurafenib also increased expression of HLA class I and HLA-E molecules, likely leading to higher engagement of inhibitory receptors (KIRs and NKG2A, respectively), and decreased lysis of vemurafenib-treated melanoma cell lines by cytokine-activated NK cells. Finally, we showed that whereas batimastat (a broad-spectrum matrix metalloprotease inhibitor) increased cell surface ULBP2 by reducing its shedding, vemurafenib lowered soluble ULBP2, indicating that BRAF signal inhibition diminished expression of both cell-surface and soluble forms of NKG2D ligands. Vemurafenib, inhibiting BRAF signaling, shifted the balance of activatory and inhibitory NK ligands on melanoma cells and displayed immunoregulatory effects on NK-cell functional activities. Cancer Immunol Res; 5(7); 582-93. ©2017 AACR. SN - 2326-6074 UR - https://www.unboundmedicine.com/medline/citation/28576831/Shifting_the_Balance_of_Activating_and_Inhibitory_Natural_Killer_Receptor_Ligands_on_BRAFV600E_Melanoma_Lines_with_Vemurafenib_ DB - PRIME DP - Unbound Medicine ER -