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

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 <i>STAT3</i> and <i>TP53</i> (15%), followed by <i>JAK3</i> and <i>JAK1</i> (6%) and <i>SOCS1</i> (4%). A high prevalence of <i>STAT3</i> mutation (21%) was observed specifically in NKTL. Novel <i>STAT3</i> mutations (p.D427H, E616G, p.E616K, and p.E696K) were shown to increase STAT3 phosphorylation and transcriptional activity of <i>STAT3</i> 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 <i>STAT3</i> mutations, and similar findings were observed by the overexpression of p.E616K and p.E616G in the <i>STAT3</i> wild-type NKTL cell line. Conversely, STAT3 silencing and inhibition decreased PD-L1 expression in <i>STAT3</i> 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.