Journal article

Publication year: 2023

Pages: 421-434

Journal: Cancer Immunology Research

Volume number: 11

Issue number: 4

ISSN: 2326-6066

eISSN: 2326-6074

Open access status: Green

DOI Link: https://doi.org/10.1158/2326-6066.CIR-22-0398

Publisher: American Association for Cancer Research

Abstract: 
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 (Panc(OVA)), compared with wild-type OT-1 CTLs. Transferred intratumoral IL18R-deficient CTLs expressed higher levels of effector cytokines TNF and IFN gamma 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.

Harvard Citation style: Lutz, V., Hellmund, V., Picard, F., Raifer, H., Ruckenbrod, T., Klein, M., et al. (2023) IL18 Receptor Signaling Regulates Tumor-Reactive CD8+ T-cell Exhaustion via Activation of the IL2/STAT5/mTOR Pathway in a Pancreatic Cancer Model, Cancer Immunology Research, 11(4), pp. 421-434. https://doi.org/10.1158/2326-6066.CIR-22-0398

APA Citation style: Lutz, V., Hellmund, V., Picard, F., Raifer, H., Ruckenbrod, T., Klein, M., Bopp, T., Savai, R., Duewell, P., Keber, C., Weigert, A., Chung, H., Buchholz, M., Menke, A., Gress, T., Huber, M., & Bauer, C. (2023). IL18 Receptor Signaling Regulates Tumor-Reactive CD8+ T-cell Exhaustion via Activation of the IL2/STAT5/mTOR Pathway in a Pancreatic Cancer Model. Cancer Immunology Research. 11(4), 421-434. https://doi.org/10.1158/2326-6066.CIR-22-0398