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Gut. 2018 Feb;67(2):320-332. doi: 10.1136/gutjnl-2016-311585. Epub 2016 Oct 21.

IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer.

Author information

1
Divisions of Medical Oncology and Gastroenterology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
2
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
3
Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.
4
Department of Pathology, The Ohio State University, Columbus, Ohio, USA.
5
Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.
6
Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA.
7
Department of Surgery (Indiana University) and IU Simon Cancer Center, The Ohio State University, Columbus, Ohio, USA.
8
Division of Surgical Oncology, Department of Surgery, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio, USA.
9
Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, Arizona, USA.
10
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.

Abstract

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.

KEYWORDS:

IMMUNOTHERAPY; INTERLEUKINS; PANCREATIC CANCER

PMID:
27797936
PMCID:
PMC5406266
DOI:
10.1136/gutjnl-2016-311585
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Competing interests: None declared.

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