American Association for Cancer Research
cir-22-0398_supplementary_data_suppst1-st3_sf1-sf6.pdf (1.48 MB)

Supplementary Data from IL18 Receptor Signaling Regulates Tumor-Reactive CD8+ T-cell Exhaustion via Activation of the IL2/STAT5/mTOR Pathway in a Pancreatic Cancer Model

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journal contribution
posted on 2023-04-03, 08:40 authored by Veronika Lutz, Veronique M. Hellmund, Felix S.R. Picard, Hartmann Raifer, Teresa Ruckenbrod, Matthias Klein, Tobias Bopp, Rajkumar Savai, Peter Duewell, Corinna U. Keber, Andreas Weigert, Ho-Ryun Chung, Malte Buchholz, André Menke, Thomas M. Gress, Magdalena Huber, Christian Bauer

Supplementary Table S1-3 and Figures S1-6


Deutsche Forschungsgemeinschaft (DFG)

Von-Behring-Röntgen-Stiftung (Von Behring-Röntgen-Foundation)



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

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