Lutz Veronika, Hellmund Veronique M, Picard Felix S R, Raifer Hartmann, Ruckenbrod Teresa, Klein Matthias, Bopp Tobias, Savai Rajkumar, Duewell Peter, Keber Corinna U, Weigert Andreas, Chung Ho-Ryun, Buchholz Malte, Menke André, Gress Thomas M, Huber Magdalena, Bauer Christian
Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, Center for Tumor and Immunology (ZTI), Philipps University Marburg, Marburg, Germany.
Institute of Systems Immunology, Philipps University Marburg, Marburg, Germany.
Cancer Immunol Res. 2023 Apr 3;11(4):421-434. doi: 10.1158/2326-6066.CIR-22-0398.
Intratumoral cytotoxic CD8+ T cells (CTL) enter a dysfunctional state characterized by expression of coinhibitory receptors, loss of effector function, and changes in the transcriptional landscape. Even though several regulators of T-cell exhaustion have been identified, the molecular mechanisms inducing T-cell exhaustion remain unclear. Here, we show that IL18 receptor (IL18R) signaling induces CD8+ T-cell exhaustion in a murine pancreatic cancer model. Adoptive transfer of Il18r-/- OT-1 CD8+ CTLs resulted in enhanced rejection of subcutaneous tumors expressing ovalbumin (OVA) as a model antigen (PancOVA), compared with wild-type OT-1 CTLs. Transferred intratumoral IL18R-deficient CTLs expressed higher levels of effector cytokines TNF and IFNγ and had reduced expression of coinhibitory receptors (PD-1, TIM-3, 2B4, LAG-3) and the transcription factors Eomes and TOX. Lower expression of coinhibitory receptors and TOX on IL18R-deficient versus IL18R-sufficient CD8+ T cells were confirmed in an orthotopic KPC model. IL18R-induced T-cell exhaustion was regulated by IL2/STAT5 and AKT/mTOR pathways, as demonstrated in an in vitro exhaustion assay. Concordantly, mice deficient in NLRP3, the molecular complex activating IL18, had decreased expression of coinhibitory receptors on intratumoral T cells and similar changes in signaling pathways at the transcriptome level. Thus, molecular pathways promoting T-cell exhaustion indicate an involvement of an NLRP3-expressing tumor microenvironment, which mediates IL18 release. The Cancer Genome Atlas analysis of patients with pancreatic carcinoma showed an association between NLRP3-mediated IL18 signaling and shorter survival. These findings indicate NLRP3-mediated IL18R signaling as a regulator of intratumoral T-cell exhaustion and a possible target for immunotherapy. See related Spotlight by Stromnes, p. 400.
肿瘤内细胞毒性CD8+ T细胞（CTL）进入功能失调状态，其特征为共抑制受体的表达、效应功能的丧失以及转录格局的变化。尽管已经鉴定出几种T细胞耗竭的调节因子，但诱导T细胞耗竭的分子机制仍不清楚。在这里，我们表明IL18受体（IL18R）信号在小鼠胰腺癌模型中诱导CD8+ T细胞耗竭。与野生型OT-1 CTL相比，过继转移Il18r-/- OT-1 CD8+ CTL可增强对表达卵清蛋白（OVA）作为模型抗原的皮下肿瘤（PancOVA）的排斥反应。转移到肿瘤内的IL18R缺陷型CTL表达更高水平的效应细胞因子TNF和IFNγ，并且共抑制受体（PD-1、TIM-3、2B4、LAG-3）以及转录因子Eomes和TOX的表达降低。在原位KPC模型中证实，与IL18R充足的CD8+ T细胞相比，IL18R缺陷型CD8+ T细胞上共抑制受体和TOX的表达更低。如体外耗竭试验所示，IL18R诱导的T细胞耗竭受IL2/STAT5和AKT/mTOR途径调节。同样，缺乏激活IL18的分子复合物NLRP3的小鼠，其肿瘤内T细胞上共抑制受体的表达降低，并且在转录组水平上信号通路也有类似变化。因此，促进T细胞耗竭的分子途径表明表达NLRP3的肿瘤微环境参与其中，该微环境介导IL18的释放。对胰腺癌患者的癌症基因组图谱分析显示，NLRP3介导的IL18信号与较短生存期之间存在关联。这些发现表明NLRP3介导的IL18R信号是肿瘤内T细胞耗竭的调节因子，也是免疫治疗的一个可能靶点。见Stromnes的相关聚焦文章，第400页。
