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IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer.
- Source :
-
Gut [Gut] 2018 Feb; Vol. 67 (2), pp. 320-332. Date of Electronic Publication: 2016 Oct 21. - Publication Year :
- 2018
-
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.<br />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 (Kras <superscript>LSL-G12D</superscript> , Trp53 <superscript>LSL-R270H</superscript> , Pdx1-cre, Brca2 <superscript>F/F</superscript> (KPC-Brca2 mice)). Systemic and local changes in immunophenotype were measured by flow cytometry or immunohistochemical analysis.<br />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 <superscript>-</superscript> CD44 <superscript>-</superscript> ). 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).<br />Conclusions: These preclinical results indicate that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in PDAC.<br />Competing Interests: Competing interests: None declared.<br /> (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)
- Subjects :
- Actins metabolism
Animals
Antineoplastic Agents, Immunological administration & dosage
B7-H1 Antigen immunology
B7-H1 Antigen metabolism
Carcinoma, Pancreatic Ductal immunology
Carcinoma, Pancreatic Ductal metabolism
Disease Models, Animal
Disease Progression
Female
Humans
Hyaluronan Receptors metabolism
Interleukin-6 immunology
Interleukin-6 metabolism
Janus Kinases metabolism
L-Selectin metabolism
Lymphocytes, Tumor-Infiltrating metabolism
Mice
Mice, Inbred C57BL
Pancreatic Neoplasms immunology
Pancreatic Neoplasms metabolism
Pancreatic Stellate Cells immunology
Pancreatic Stellate Cells metabolism
STAT Transcription Factors metabolism
Survival Rate
Th1 Cells metabolism
Tumor Microenvironment immunology
Xenograft Model Antitumor Assays
Antineoplastic Combined Chemotherapy Protocols therapeutic use
B7-H1 Antigen antagonists & inhibitors
Carcinoma, Pancreatic Ductal drug therapy
Interleukin-6 antagonists & inhibitors
Pancreatic Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1468-3288
- Volume :
- 67
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Gut
- Publication Type :
- Academic Journal
- Accession number :
- 27797936
- Full Text :
- https://doi.org/10.1136/gutjnl-2016-311585