Regulation of PD-L1 expression in non–small cell lung cancer by interleukin-1β

IntroductionProgrammed cell death–ligand 1 (PD-L1) is a biomarker for prediction of the clinical efficacy of immune checkpoint inhibitors in various cancer types. The role of cytokines in regulation of PD-L1 expression in tumor cells has not been fully characterized, however. Here we show that interleukin-1β (IL-1β) plays a key role in regulation of PD-L1 expression in non–small cell lung cancer (NSCLC).MethodsWe performed comprehensive screening of cytokine gene expression in NSCLC tissue using available single-cell RNA-Sequence data. Then we examined the role of IL-1β in vitro to elucidate its induction of PD-L1 on NSCLC cells.ResultsThe IL-1β gene is highly expressed in the tumor microenvironment, particularly in macrophages. The combination of IL-1β and interferon-γ (IFN-γ) induced a synergistic increase in PD-L1 expression in NSCLC cell lines. IL-1β and IFN-γ also cooperatively activated mitogen-activated protein kinase (MAPK) signaling and promoted the binding of downstream transcription factors to the PD-L1 gene promoter. Furthermore, inhibitors of MAPK signaling blocked upregulation of PD-L1 by IL-1β and IFN-γ.DiscussionOur study reports high levels of IL-1β in the tumor microenvironment may cooperate with IFN-γ to induce maximal PD-L1 expression in tumor cells via activation of MAPK signaling, with the IL-1β–MAPK axis being a promising therapeutic target for attenuation of PD-L1–mediated suppression of antitumor immunity

Stress rotations and the long-term weakness of the Median Tectonic Line and the Rokko-Awaji Segment

International audienceWe used a field analysis of rock deformation microstructures and mesostructures to reconstructthe long-term orientation of stresses around two major active fault systems in Japan, the Median TectonicLine and the Rokko-Awaji Segment. Our study reveals that the dextral slip of the two fault systems, activesince the Plio-Quaternary, was preceded by fault normal extension in the Miocene and sinistral wrenching inthe Paleogene. The two fault systems deviated the regional stress field at the kilometer scale in their vicinityduring each of the three tectonic regimes. The largest deviation, found in the Plio-Quaternary, is a more faultnormal rotation of the maximum horizontal stress to an angle of 79° with the fault strands, suggesting anextremely low shear stress on the Median Tectonic Line and the Rokko-Awaji Segment. Possible causes of thislong-term stress perturbation include a nearly total release of shear stress during earthquakes, a low staticfriction coefficient, or lowelastic properties of the fault zones comparedwith the country rock. Independently ofthe preferred interpretation, the nearly fault normal orientation of the direction of maximum compressionsuggests that the mechanical properties of the fault zones are inadequate for the buildup of a pore fluidpressure sufficiently elevated to activate slip. The long-term weakness of the Median Tectonic Line and theRokko-Awaji Segment may reside in low-friction/low-elasticity materials or dynamic weakening rather than inpreearthquake fluid overpressures