IL18 Receptor Signaling Inhibits Intratumoral CD8+ T-Cell Migration in a Murine Pancreatic Cancer Model

Author:

Nasiri Elena1,Student Malte12,Roth Katrin3,Siti Utami Nadya1,Huber Magdalena4ORCID,Buchholz Malte1,Gress Thomas M.1ORCID,Bauer Christian1ORCID

Affiliation:

1. Department of Gastroenterology, Endocrinology, Infectious Diseases and Metabolism, University Hospital Marburg, Philipps University Marburg, 35043 Marburg, Germany

2. Department of Internal Medicine I, University Hospital Ulm, 89081 Ulm, Germany

3. Core Facility Cellular Imaging, Center for Tumor Biology and Immunology, Philipps University Marburg, 35043 Marburg, Germany

4. Institute for Medical Microbiology and Hospital Hygiene, Philipps University Marburg, 35043 Marburg, Germany

Abstract

In pancreatic ductal adenocarcinoma (PDAC), the infiltration of CD8+ cytotoxic T cells (CTLs) is an important factor in determining prognosis. The migration pattern and interaction behavior of intratumoral CTLs are pivotal to tumor rejection. NLRP3-dependent proinflammatory cytokines IL-1β and IL-18 play a prominent role for CTL induction and differentiation. Here, we investigate the effects of T-cellular IL-1R and IL-18R signaling for intratumoral T-cell motility. Murine adenocarcinoma cell line Panc02 was stably transfected with ovalbumin (OVA) and fluorophore H2B-Cerulean to generate PancOVA H2B-Cerulean tumor cells. Dorsal skinfold chambers (DSFC) were installed on wild-type mice, and PancOVA H2B-Cerulean tumor cells were implanted into the chambers. PancOVA spheroids were formed using the Corning® Matrigel®-based 3D cell culture technique. CTLs were generated from OT-1 mice, Il1r−/− OT-1 mice, or Il18r−/− OT-1 mice and were marked with fluorophores. This was followed by the adoptive transfer of CTLs into tumor-bearing mice or the application into tumor spheroids. After visualization with multiphoton microscopy (MPM), Imaris software was used to perform T-cell tracking. Imaris analysis indicates a significantly higher accumulation of Il18r−/− CTLs in PancOVA tumors and a significant reduction in tumor volume compared to wild-type CTLs. Il18r−/− CTLs covered a longer distance (track displacement length) in comparison to wild-type (WT) CTLs, and had a higher average speed (mean track speed). The analysis of instantaneous velocity suggests a higher percentage of arrested tracks (arrests: <4 μm/min) for Il18r−/− CTLs. Our data indicate the contribution of IL-18R signaling to T-cell effector strength, warranting further investigation on phenomena such as intratumoral T-cell exhaustion.

Funder

DFG

Behring-Röntgen-Foundation

Publisher

MDPI AG

Subject

General Medicine

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