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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Antineoplastic Agents, Immunological / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • B7-H1 Antigen / antagonists & inhibitors*
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Humans
  • Hyaluronan Receptors / metabolism
  • Interleukin-6 / antagonists & inhibitors*
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism
  • Janus Kinases / metabolism
  • L-Selectin / metabolism
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Pancreatic Neoplasms / drug therapy*
  • 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

Substances

  • Actins
  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Hyaluronan Receptors
  • Interleukin-6
  • STAT Transcription Factors
  • alpha-smooth muscle actin, mouse
  • interleukin-6, mouse
  • L-Selectin
  • Janus Kinases