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

• DOI: 10.1158/2326-6066.c.6534760.v1
• Publication Date: 2023-04-03T13:45:59Z
• Authors: Veronika Lutz; Veronique M. Hell...; 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

<div>Abstract<p>Intratumoral cytotoxic CD8<sup>+</sup> T cells (CTL) enter a dysfunctional state characterized by expression of coinhibitory receptors, loss effector function, and changes in the transcriptional landscape. Even though several regulators T-cell exhaustion have been identified, molecular mechanisms inducing remain unclear. Here, we show that IL18 receptor (IL18R) signaling induces murine pancreatic cancer model. Adoptive transfer <i>Il18r<sup>−/−</sup></i> OT-1 CTLs resulted enhanced rejection subcutaneous tumors expressing ovalbumin (OVA) as model antigen (Panc<sup>OVA</sup>), compared with wild-type CTLs. Transferred intratumoral IL18R-deficient expressed higher levels cytokines TNF IFNγ had reduced receptors (PD-1, TIM-3, 2B4, LAG-3) transcription factors Eomes TOX. Lower TOX on versus IL18R-sufficient were confirmed an orthotopic KPC IL18R-induced was regulated IL2/STAT5 AKT/mTOR pathways, demonstrated <i>in vitro</i> assay. Concordantly, mice deficient NLRP3, complex activating IL18, decreased similar pathways at transcriptome level. Thus, promoting indicate involvement NLRP3-expressing tumor microenvironment, which mediates release. The Cancer Genome Atlas analysis patients carcinoma showed association between NLRP3-mediated shorter survival. These findings IL18R regulator possible target for immunotherapy.</p><p><i><a href="https://aacrjournals.org/cancerimmunolres/article/doi/10.1158/2326-6066.CIR-23-0145" target="_blank">See related Spotlight Stromnes, p. 400</a></i></p></div>