Aberrant CD137 ligand expression induced by GATA6 overexpression promotes tumor progression in cutaneous T-cell lymphoma

Abstract

CD137 and its ligand, CD137L, are expressed on activated T cells and antigen-presenting cells, respectively. Recent studies have shown that CD137L and CD137 are aberrantly expressed by tumor cells, especially in some hematopoietic malignancies, and interactions between these molecules on tumor cells promote tumor growth. In this study, we investigated the roles of CD137L and CD137 in cutaneous T-cell lymphoma (CTCL), represented by mycosis fungoides and Sézary syndrome. Flow cytometric analysis showed that primary Sézary cells and CTCL cell lines (Hut78, MyLa, HH, SeAx, and MJ) aberrantly expressed CD137L. CD137L expression by tumor cells in CTCL was also confirmed by immunohistochemistry. Anti-CD137L-neutralizing antibody inhibited proliferation, survival, CXCR4-mediated migration, and in vivo growth in CTCL cell lines through inhibition of phosphorylation of AKT, extracellular signal-regulated kinase 1/2, p38 MAPK, and JNK. Moreover, suppression of CD137L signaling decreased antiapoptotic proteins Bcl-2 and phosphorylated Bad. We also explored the transcription factor regulating CD137L expression. Because GATA6 has been proposed as an oncogene in many types of tumors with aberrant CD137L expression, we examined GATA6 expression and the involvement of GATA6 in CD137L expression in CTCL. DNA hypomethylation and histone acetylation induced GATA6 overexpression in CTCL cells. Furthermore, chromatin immunoprecipitation, luciferase reporter assay, and knockdown by short hairpin RNA showed that GATA6 directly upregulated CD137L expression. Inhibition of GATA6 resulted in decreased survival and in vivo growth in CTCL cells. Collectively, our findings prompt a novel therapeutic approach to CTCL based on the discovery that the GATA6/CD137L axis plays an important role in the tumorigenesis of CTCL.

Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells

“…Supporting this assumption, CD137L is expressed by T cells and was shown to induce T cell trans-costimulation resulting in potent tumor rejection (Stephan et al, 2007). Furthermore, EBV-unrelated cutaneous T cell lymphomas have been shown to express significant amount of CD137L (Kamijo et al, 2018). The recent description of EBV-driven B cell lymphomas in two patients with CD137 deficiency is strongly in favor of a key role of CD137 in immunity to EBV (Alosaimi et al, 2019), although the clinical asymptomatic feature of the sister (in our study) suggests incomplete penetrance.…”

Multiple roles and regulatory mechanisms of the transcription factor GATA6 in human cancers

“…In addition, according to a recent study on cutaneous T‐cell lymphoma (CTCL), GATA6 directly up‐regulates CD137L expression and promotes tumor growth . In a study of animal models of sebaceous gland (SG) tumors, Gata6 was found to control sebaceous gland development and cancer .…”

“…100 In addition, according to a recent study on cutaneous T-cell lymphoma (CTCL), GATA6 directly up-regulates CD137L expression and promotes tumor growth. 101 In a study of animal models of sebaceous gland (SG) tumors, Gata6 was found to control sebaceous gland development and cancer. 102 Because GATA6 can be differentially expressed in prostate cancer, GATA6 can be used not only as a candidate biomarker for prostate cancer, but also as a potential therapeutic target.…”

Development and validation of a novel stem cell subtype for bladder cancer based on stem genomic profiling

“…Therefore, GATA3 may act as a tumor suppressor gene in BLCA. GRHL2 and GATA6 play important regulatory roles in many life activities such as embryonic development, damage repair, epidermal barrier formation, tracheal epithelial formation, and neural tube development, but they also play an important role in the occurrence and development of tumors, cell proliferation, invasion, and metastasis are closely related, which were verified in the relevant pathways identified in the black module [39][40][41][42][43][44][45] ( Figure 10D-E). Thus, we identified GATA3 and GATA6 as important transcription factors with opposite expression and effects on prognosis in patients with different BLCA stem cell subtypes ( Figure 10F-I).…”