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Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma
- Source :
- Blood. 132(11)
- Publication Year :
- 2018
-
Abstract
- Mature T-cell lymphomas, including peripheral T-cell lymphoma (PTCL) and extranodal NK/T-cell lymphoma (NKTL), represent a heterogeneous group of non-Hodgkin lymphomas with dismal outcomes and limited treatment options. To determine the extent of involvement of the JAK/STAT pathway in this malignancy, we performed targeted capture sequencing of 188 genes in this pathway in 171 PTCL and NKTL cases. A total of 272 nonsynonymous somatic mutations in 101 genes were identified in 73% of the samples, including 258 single-nucleotide variants and 14 insertions or deletions. Recurrent mutations were most frequently located in STAT3 and TP53 (15%), followed by JAK3 and JAK1 (6%) and SOCS1 (4%). A high prevalence of STAT3 mutation (21%) was observed specifically in NKTL. Novel STAT3 mutations (p.D427H, E616G, p.E616K, and p.E696K) were shown to increase STAT3 phosphorylation and transcriptional activity of STAT3 in the absence of cytokine, in which p.E616K induced programmed cell death-ligand 1 (PD-L1) expression by robust binding of activated STAT3 to the PD-L1 gene promoter. Consistent with these findings, PD-L1 was overexpressed in NKTL cell lines harboring hotspot STAT3 mutations, and similar findings were observed by the overexpression of p.E616K and p.E616G in the STAT3 wild-type NKTL cell line. Conversely, STAT3 silencing and inhibition decreased PD-L1 expression in STAT3 mutant NKTL cell lines. In NKTL tumors, STAT3 activation correlated significantly with PD-L1 expression. We demonstrated that STAT3 activation confers high PD-L1 expression, which may promote tumor immune evasion. The combination of PD-1/PD-L1 antibodies and STAT3 inhibitors might be a promising therapeutic approach for NKTL, and possibly PTCL. ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore)
- Subjects :
- 0301 basic medicine
STAT3 Transcription Factor
Somatic cell
Immunology
Mutation, Missense
Biology
Biochemistry
B7-H1 Antigen
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
medicine
Anaplastic lymphoma kinase
Gene silencing
Humans
Anaplastic Lymphoma Kinase
Science::Medicine [DRNTU]
Regulation of gene expression
Lymphoid Neoplasia
Suppressor of cytokine signaling 1
JAK-STAT signaling pathway
Ephrin Receptor A3
Cell Biology
Hematology
Natural killer T cell
medicine.disease
Lymphoma
Neoplasm Proteins
Gene Expression Regulation, Neoplastic
Lymphoma, Extranodal NK-T-Cell
030104 developmental biology
Amino Acid Substitution
030220 oncology & carcinogenesis
Cancer research
Signal Transduction
Subjects
Details
- ISSN :
- 15280020
- Volume :
- 132
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....4ce3cdc089fca9d745259e9e2a2309bd