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

Thomas A. Mace, Reena Shakya, Jason R. Pitarresi, Benjamin J Swanson, Christopher W. McQuinn, Shannon Loftus, Emily Nordquist, Zobeida Cruz-Monserrate, Lianbo Yu, Gregory Young, Xiaoling Zhong, Teresa A. Zimmers, Michael C. Ostrowski, Thomas Ludwig, Mark Bloomston, Tanios Bekaii-Saab, Gregory B. Lesinski

Research output: Contribution to journalArticle

67 Citations (Scopus)

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 (PDL1) 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 a-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.

Original languageEnglish (US)
JournalGut
DOIs
StateAccepted/In press - Oct 21 2016
Externally publishedYes

Fingerprint

Pancreatic Neoplasms
Interleukin-6
Antibodies
Neoplasms
Adenocarcinoma
Pancreatic Stellate Cells
Therapeutics
T-Lymphocytes
Smooth Muscle Myocytes
Actins
Flow Cytometry
Immunohistochemistry
Ligands
Cell Line
Survival

ASJC Scopus subject areas

  • Gastroenterology

Cite this

IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. / Mace, Thomas A.; Shakya, Reena; Pitarresi, Jason R.; Swanson, Benjamin J; McQuinn, Christopher W.; Loftus, Shannon; Nordquist, Emily; Cruz-Monserrate, Zobeida; Yu, Lianbo; Young, Gregory; Zhong, Xiaoling; Zimmers, Teresa A.; Ostrowski, Michael C.; Ludwig, Thomas; Bloomston, Mark; Bekaii-Saab, Tanios; Lesinski, Gregory B.

In: Gut, 21.10.2016.

Research output: Contribution to journalArticle

Mace, TA, Shakya, R, Pitarresi, JR, Swanson, BJ, McQuinn, CW, Loftus, S, Nordquist, E, Cruz-Monserrate, Z, Yu, L, Young, G, Zhong, X, Zimmers, TA, Ostrowski, MC, Ludwig, T, Bloomston, M, Bekaii-Saab, T & Lesinski, GB 2016, 'IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer', Gut. https://doi.org/10.1136/gutjnl-2016-311585
Mace, Thomas A. ; Shakya, Reena ; Pitarresi, Jason R. ; Swanson, Benjamin J ; McQuinn, Christopher W. ; Loftus, Shannon ; Nordquist, Emily ; Cruz-Monserrate, Zobeida ; Yu, Lianbo ; Young, Gregory ; Zhong, Xiaoling ; Zimmers, Teresa A. ; Ostrowski, Michael C. ; Ludwig, Thomas ; Bloomston, Mark ; Bekaii-Saab, Tanios ; Lesinski, Gregory B. / IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. In: Gut. 2016.
@article{cf56d09535c84cbbbef8efec16c193d7,
title = "IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer",
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 (PDL1) 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 a-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.",
author = "Mace, {Thomas A.} and Reena Shakya and Pitarresi, {Jason R.} and Swanson, {Benjamin J} and McQuinn, {Christopher W.} and Shannon Loftus and Emily Nordquist and Zobeida Cruz-Monserrate and Lianbo Yu and Gregory Young and Xiaoling Zhong and Zimmers, {Teresa A.} and Ostrowski, {Michael C.} and Thomas Ludwig and Mark Bloomston and Tanios Bekaii-Saab and Lesinski, {Gregory B.}",
year = "2016",
month = "10",
day = "21",
doi = "10.1136/gutjnl-2016-311585",
language = "English (US)",
journal = "Gut",
issn = "0017-5749",
publisher = "BMJ Publishing Group",

}

TY - JOUR

T1 - IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer

AU - Mace, Thomas A.

AU - Shakya, Reena

AU - Pitarresi, Jason R.

AU - Swanson, Benjamin J

AU - McQuinn, Christopher W.

AU - Loftus, Shannon

AU - Nordquist, Emily

AU - Cruz-Monserrate, Zobeida

AU - Yu, Lianbo

AU - Young, Gregory

AU - Zhong, Xiaoling

AU - Zimmers, Teresa A.

AU - Ostrowski, Michael C.

AU - Ludwig, Thomas

AU - Bloomston, Mark

AU - Bekaii-Saab, Tanios

AU - Lesinski, Gregory B.

PY - 2016/10/21

Y1 - 2016/10/21

N2 - 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 (PDL1) 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 a-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.

AB - 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 (PDL1) 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 a-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.

UR - http://www.scopus.com/inward/record.url?scp=84994516325&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84994516325&partnerID=8YFLogxK

U2 - 10.1136/gutjnl-2016-311585

DO - 10.1136/gutjnl-2016-311585

M3 - Article

JO - Gut

JF - Gut

SN - 0017-5749

ER -