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

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 and Choon-Kiat Ong

Key points

  • Alterations in JAK/STAT signaling pathway are highly prevalent in PTCL and NKTL where STAT3 and TP53 are the most frequently mutated genes.

  • STAT3 activation drives PD-L1 expression in NKTL, providing rationale to combine STAT3 inhibitors with immune checkpoint inhibitors.

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 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 non-synonymous 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 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 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.

  • Submitted January 25, 2018.
  • Accepted July 17, 2018.