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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Carcinoma, Pancreatic Ductal/drug therapy , Interleukin-6/antagonists & inhibitors , Pancreatic Neoplasms/drug therapy , 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 AssaysABSTRACT
Linear and crosslinked polyanhydrides can be made using photoinitiated thiol-ene chemistry, a simple and effective method of making crosslinked structures that have surface degradation characteristics.
