STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity

Abstract

Natural killer (NK) cells are important components of the innate immune defense against infections and cancers. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that is essential for NK cell maturation and NK cell-dependent tumor surveillance. Two alternatively spliced isoforms of STAT1 exist: a full-length STAT1α and a C-terminally truncated STAT1β isoform. Aberrant splicing is frequently observed in cancer cells and several anti-cancer drugs interfere with the cellular splicing machinery. To investigate whether NK cell-mediated tumor surveillance is affected by a switch in STAT1 splicing, we made use of knock-in mice expressing either only the STAT1α (Stat1 α/α) or the STAT1β (Stat1 β/β) isoform. NK cells from Stat1 α/α mice matured normally and controlled transplanted tumor cells as efficiently as NK cells from wild-type mice. In contrast, NK cells from Stat1 β/β mice showed impaired maturation and effector functions, albeit less severe than NK cells from mice that completely lack STAT1 (Stat1 −/−). Mechanistically, we show that NK cell maturation requires the presence of STAT1α in the niche rather than in NK cells themselves and that NK cell maturation depends on IFNγ signaling under homeostatic conditions. The impaired NK cell maturation in Stat1 β/β mice was paralleled by decreased IL-15 receptor alpha (IL-15Rα) surface levels on dendritic cells, macrophages and monocytes. Treatment of Stat1 β/β mice with exogenous IL-15/IL-15Rα complexes rescued NK cell maturation but not their effector functions. Collectively, our findings provide evidence that STAT1 isoforms are not functionally redundant in regulating NK cell activity and that the absence of STAT1α severely impairs, but does not abolish, NK cell-dependent tumor surveillance.

An Immune Checkpoint-Related Gene Signature for Predicting Survival of Pediatric Acute Myeloid Leukemia

“…In several forms of human cancer, such as breast cancers, pleural mesothelioma, head and neck cancer, and lymphoma, aberrant activation STAT1 has been identified [ 31 ]. In the majority of trials, high expression of STAT1 leads to improved clinical outcomes, but contradictive data has been shown suggesting that the clinical findings of cancer patients with high expression of STAT1 and/or pSTAT1 are poorer as contrasted with low expression patients [ 31 ]. Recent research showed that the eIF4F-STAT1-PD-L1 axis in melanoma is associated with immune evasion [ 32 ].…”

Eomes and T‐bet, a dynamic duo regulating NK cell differentiation

“…[21] IL-12-activated STAT4 is also known to turn on Tbet in NK cells, [22] while STAT1 is essential for optimal T-bet expression and terminal NK cell maturation. [23,24] IL-12 can repress Eomes expression in activated CD8 T cells, [25] while TGF-β represses both Tbet and Eomes expression in NK cells. [26][27][28] Finally, IL-4 expression by thymic NKT cells can turn on Eomes expression in developing T cells and lead to their differentiation into "innate memory" T cells.…”

“…[55] Zeb2 also influences binding of Tbet at few sites as shown by ChIP-seq of T-bet in WT and Zeb2 deficient CTLs. [55] T-bet may potentially interact with other TFs associated with the mature NK cell program such as STAT1, [24] KLF2, [69,70] or IRF2. [71] Our ChIP-seq analyses also suggested a specific interaction of T-bet with STAT4.…”

Epigenetic Regulation of NK Cell-Mediated Antitumor Immunity

“…Inhibition of upstream cyclin-dependent kinase 8 (CDK8) may be a therapeutic strategy for stimulating NK cell-mediated tumor surveillance ( 102 ). Full-length STAT1α is efficient for NK cell maturation and tumor control in mice, while NK cells from the C-terminally truncated STAT1β isoform show impaired maturation and effector functions ( 103 ). STAT-3 regulates all aspects of NK biology, including almost all of the pathways for target cell killing and the reciprocal regulatory interaction between NK cells and other components of the immune system, which has been presented in detail by Nicholas A. Cacalono ( 104 ).…”