title: IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  These preclinical results indicate that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in PDAC.
authors: Divisions of Medical Oncology and Gastroenterology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
authors: Thomas A
authors: TA
authors: Mace
authors: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
authors: Reena
authors: R
authors: Shakya
authors: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.
authors: Jason R
authors: JR
authors: Pitarresi
authors: Department of Pathology, The Ohio State University, Columbus, Ohio, USA.
authors: Benjamin
authors: B
authors: Swanson
authors: Divisions of Medical Oncology and Gastroenterology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
authors: Christopher W
authors: CW
authors: McQuinn
authors: Divisions of Medical Oncology and Gastroenterology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
authors: Shannon
authors: S
authors: Loftus
authors: Divisions of Medical Oncology and Gastroenterology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
authors: Emily
authors: E
authors: Nordquist
authors: Divisions of Medical Oncology and Gastroenterology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
authors: Zobeida
authors: Z
authors: Cruz-Monserrate
authors: Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.
authors: Lianbo
authors: L
authors: Yu
authors: Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA.
authors: Gregory
authors: G
authors: Young
authors: Department of Surgery (Indiana University) and IU Simon Cancer Center, The Ohio State University, Columbus, Ohio, USA.
authors: Xiaoling
authors: X
authors: Zhong
authors: Department of Surgery (Indiana University) and IU Simon Cancer Center, The Ohio State University, Columbus, Ohio, USA.
authors: Teresa A
authors: TA
authors: Zimmers
authors: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.
authors: Michael C
authors: MC
authors: Ostrowski
authors: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.
authors: Thomas
authors: T
authors: Ludwig
authors: 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.
authors: Mark
authors: M
authors: Bloomston
authors: Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, Arizona, USA.
authors: Tanios
authors: T
authors: Bekaii-Saab
authors: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
authors: Gregory B
authors: GB
authors: Lesinski
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D058954:Pancreatic Stellate Cells / Q000276:immunology / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015996:Survival Rate; D018417:Th1 Cells / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology; D023041:Xenograft Model Antitumor Assays; D000093242:Interleukin-6 Inhibitors
chemical_list: D000199:Actins; D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; D018960:Hyaluronan Receptors; D015850:Interleukin-6; D053612:Janus Kinases; D019041:L-Selectin; D050791:STAT Transcription Factors; D000093242:Interleukin-6 Inhibitors; C498919:Cd274 protein, mouse; C544013:alpha-smooth muscle actin, mouse; C577686:interleukin-6, mouse
keywords: IMMUNOTHERAPY; INTERLEUKINS; PANCREATIC CANCER