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

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

Blood

10.1182/blood-2018-01-829424

https://doi.org/10.1182/blood-2018-01-829424

Tammy Linlin Song, Maarja-Liisa Nairismägi, Yurike Laurensia, Jing-Quan Lim, Jing Tan, Zhi-Mei Li, Wan-Lu Pang, Atish Kizhakeyil, Giovani-Claresta Wijaya, Da-Chuan Huang, Sanjanaa Nagarajan, Burton Kuan-Hui Chia, Daryl Cheah, Yan-Hui Liu, Fen Zhang, Hui-Lan Rao, Tiffany Tang, Esther Kam-Yin Wong, Jin-Xin Bei, Jabed Iqbal, Nicholas-Francis Grigoropoulos, Siok-Bian Ng, Wee-Joo Chng, Bin-Tean Teh, Soo-Yong Tan, Navin Kumar Verma, Hao Fan, Soon-Thye Lim, Choon-Kiat Ong

13 September 2018

ammy Linlin Song, Maarja-Liisa Nairismägi, Yurike Laurensia, Jing-Quan Lim, Jing Tan, Zhi-Mei Li, Wan-Lu Pang, Atish Kizhakeyil, Giovani-Claresta Wijaya, Da-Chuan Huang, Sanjanaa Nagarajan, Burton Kuan-Hui Chia, Daryl Cheah, Yan-Hui Liu, Fen Zhang, Hui-Lan Rao, Tiffany Tang, Esther Kam-Yin Wong, Jin-Xin Bei, Jabed Iqbal, Nicholas-Francis Grigoropoulos, Siok-Bian Ng, Wee-Joo Chng, Bin-Tean Teh, Soo-Yong Tan, Navin Kumar Verma, Hao Fan, Soon-Thye Lim, Choon-Kiat Ong; Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma. Blood 2018; 132 (11): 1146–1158. doi: https://doi.org/10.1182/blood-2018-01-829424

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.

PublisherCopyrights

This study was supported by research funding from the Singapore Ministry of Health’s National Medical Research Council, Tanoto Foundation as Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, and Singapore National Cancer Centre Research Fund, Oncology Academic Clinical Program Cancer Collaborative Scheme, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore Start-Up Grant, and Biomedical Research Council, A*STAR.

The full paper is available for download at the publisher's URL here: https://doi.org/10.1182/blood-2018-01-829424

https://oar.a-star.edu.sg/communities-collections/articles/14804

0006-4971
1528-0020

Bioinformatics Institute