Objective Limited efficacy of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) has prompted investigation into combination therapy. We hypothesised that interleukin 6 (IL-6) blockade would modulate immunological features of PDAC and enhance the efficacy of anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor therapy.
Design Transcription profiles and IL-6 secretion from primary patient-derived pancreatic stellate cells (PSCs) were analyzed via Nanostring and immunohistochemistry, respectively. In vivo efficacy and mechanistic studies were conducted with antibodies (Abs) targeting IL-6, PD-L1, CD4 or CD8 in subcutaneous or orthotopic models using Panc02, MT5 or KPC-luc cell lines; and the aggressive, genetically engineered PDAC model (KrasLSL−G12D, Trp53LSL−R270H, Pdx1-cre, Brca2F/F (KPC-Brca2 mice)). Systemic and local changes in immunophenotype were measured by flow cytometry or immunohistochemical analysis.
Results PSCs (n=12) demonstrated prominent IL-6 expression, which was localised to stroma of tumours. Combined IL-6 and PD-L1 blockade elicited efficacy in mice bearing subcutaneous MT5 (p<0.02) and Panc02 tumours (p=0.046), which was accompanied by increased intratumoural effector T lymphocytes (CD62L−CD44−). CD8-depleting but not CD4-depleting Abs abrogated the efficacy of combined IL-6 and PD-L1 blockade in mice bearing Panc02 tumours (p=0.0016). This treatment combination also elicited significant antitumour activity in mice bearing orthotopic KPC-luc tumours and limited tumour progression in KPC-Brca2 mice (p<0.001). Histological analysis revealed increased T-cell infiltration and reduced α-smooth muscle actin cells in tumours from multiple models. Finally, IL-6 and PD-L1 blockade increased overall survival in KPC-Brca2 mice compared with isotype controls (p=0.0012).
Conclusions These preclinical results indicate that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in PDAC.
- PANCREATIC CANCER
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Contributors TAM, ZC-M, MCO, MB, TB-S and GBL contributed to conception and design of the study. TAM, RS, CWM, SL, EN and XZ performed experiments and acquired data. RS, ZC-M and TL provided expertise in genetic murine models and in vivo experiments. BS provided expertise in pathological analysis. MB provided patient surgical specimens and regulatory approval. GY provided expertise in statistical analysis. GY and LY provided expertise in bioinformatics. TAM, MCO, TB-S and GBL drafted the manuscript. TAM, JRP, GY, TAZ and GBL revised the manuscript critically for important intellectual content. All authors approved the final version of the manuscript.
Funding NIH Grants 5T32CA009338-34 (Mace), 1R21AI124687-01 (Lesinski), 1R01CA208253-01 (Lesinski), P30CA016058-36 (Caligiuri), American-Italian Cancer Foundation Pancreatic Cancer Initiative grant (Bloomston) and Lustgarten Foundation grant (Zimmers). The project described was supported by Award Number UL1RR025755 from the National Center for Research Resources, funded by the Office of the Director, National Institutes of Health (OD) and supported by the NIH Roadmap for Medical Research. Supported by the William Hall Fund for pancreatic and liver research. The project was described by Award Number Grant KL2TR001068 from the National Center for Advancing Translational Sciences. This work was also supported by the Pelotonia Fellowship Program. Any opinions, findings and conclusions expressed are those of the authors and do not necessarily reflect those of the Pelotonia Fellowship Program. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences, the National Center for Research Resources or the National Institutes of Health.
Competing interests None declared.
Ethics approval The Ohio State University and Indiana University IRBs.
Provenance and peer review Not commissioned; externally peer reviewed.
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