Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma.

Autor:	Song TL; Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, and., Nairismägi ML; Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, and., Laurensia Y; Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, and., Lim JQ; Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, and., Tan J; Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, and.; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore.; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China., Li ZM; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore., Pang WL; Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, and., Kizhakeyil A; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore., Wijaya GC; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore., Huang DC; Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, and.; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore., Nagarajan S; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore., Chia BK; Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, and., Cheah D; Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, and., Liu YH; Department of Pathology, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangzhou, China., Zhang F; Department of Pathology, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangzhou, China., Rao HL; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China., Tang T; Division of Medical Oncology, National Cancer Centre Singapore, Singapore., Wong EK; Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, and., Bei JX; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China., Iqbal J; Department of Anatomical Pathology, Division of Pathology, Singapore General Hospital, Singapore.; Duke-NUS Graduate Medical School, Singapore., Grigoropoulos NF; Department of Haematology, Singapore General Hospital, Singapore., Ng SB; Department of Pathology, Yong Loo Lin School of Medicine, and.; Department of Pathology, National University Hospital, Singapore.; National University Cancer Institute of Singapore, Singapore.; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Chng WJ; National University Cancer Institute of Singapore, Singapore.; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Teh BT; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore.; Division of Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore., Tan SY; Department of Pathology, Yong Loo Lin School of Medicine, and.; Department of Pathology, National University Hospital, Singapore.; Institute of Cell and Molecular Biology and., Verma NK; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore., Fan H; Bioinformatics Institute, A*STAR, Singapore.; Department of Biological Sciences, National University of Singapore, Singapore.; Centre for Computational Biology, DUKE-NUS Graduate Medical School, Singapore., Lim ST; Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, and.; Division of Medical Oncology, National Cancer Centre Singapore, Singapore.; Office of Education, Duke-NUS Graduate Medical School, Singapore; and., Ong CK; Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, and.; Genome Institute of Singapore, A*STAR, Singapore.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2018 Sep 13; Vol. 132 (11), pp. 1146-1158. Date of Electronic Publication: 2018 Jul 27.
DOI:	10.1182/blood-2018-01-829424
Abstrakt:	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. (© 2018 by The American Society of Hematology.)
Databáze:	MEDLINE
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