Methylation of NKG2D ligands contributes to immune system evasion in acute myeloid leukemia.
Engagement of the activating receptor NKG2D (natural killer group 2 member D) with its ligands (NKG2DL) major histocompatibility complex class I related-A and -B (MICA/B), UL-16 binding protein families (ULBPs 1-6) is important to ensure the innate immunity to tumor cells. However, these cells have developed strategies to downregulate NKG2DL expression and avoid immune recognition. We demonstrate that DNA methylation can contribute to the absence of NKG2DL expression during tumor progression. We analyzed the DNA methylation profiles for each NKG2DL by pyrosequencing in acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), hepatocellular carcinoma (HC), breast cancer and colon cancer cell lines. High levels of DNA methylation for NKG2DL were found in some tumor cell lines, mainly in AML cells. This hypermethylation was correlated with the absence of transcription for NKG2DL. Higher DNA methylation levels for MICA, ULBP1 and ULBP2 were observed in AML patients (n=60) compared with healthy donors (n=25). However, no DNA methylation for NKG2DL was found in colon cancer patients (n=44). Treatment with demethylating agents (5-azacytidine and 5-aza-2'-deoxycytidine) restored the expression of NKG2DL on the cell surface of AML cells, leading to an enhanced recognition by NKG2D-expressing cells. Our data suggest that NKG2DL may be aberrantly silenced by DNA methylation as a consequence of tumor development in AML patients.
Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
A
A
Baragaño Raneros
Area of Cell Therapy, Hospital Reina Sofía, Córdoba, Spain.
V
V
Martín-Palanco
Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, Oviedo, Spain.
A F
AF
Fernandez
Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
R M
RM
Rodriguez
Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, Oviedo, Spain.
M F
MF
Fraga
1] Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain [2] Fundación Renal 'Iñigo Álvarez de Toledo', Madrid, Spain.
C
C
Lopez-Larrea
Cellular Biology of Renal Diseases Laboratory, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
B
B
Suarez-Alvarez
D045744:Cell Line, Tumor; D019175:DNA Methylation; D058851:GPI-Linked Proteins / Q000276:immunology / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000276:immunology*; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism*; D019139:Tumor Escape
D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D008024:Ligands; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K