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 Swanson, Christopher W. McQuinn, Shannon Loftus, Emily Nordquist, Zobeida Cruz-Monserrate, Lianbo Yu, Gregory Young, Xiaoling Zhong, Teresa Zimmers, Michael C. Ostrowski, Thomas Ludwig, Mark Bloomston, Tanios Bekaii-Saab, Gregory B. Lesinski

Research output: Contribution to journalArticle

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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

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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

Mace, T. A., Shakya, R., Pitarresi, J. R., Swanson, B., McQuinn, C. W., Loftus, S., ... Lesinski, G. B. (Accepted/In press). 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

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; McQuinn, Christopher W.; Loftus, Shannon; Nordquist, Emily; Cruz-Monserrate, Zobeida; Yu, Lianbo; Young, Gregory; Zhong, Xiaoling; Zimmers, Teresa; 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, B, McQuinn, CW, Loftus, S, Nordquist, E, Cruz-Monserrate, Z, Yu, L, Young, G, Zhong, X, Zimmers, T, 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 ; McQuinn, Christopher W. ; Loftus, Shannon ; Nordquist, Emily ; Cruz-Monserrate, Zobeida ; Yu, Lianbo ; Young, Gregory ; Zhong, Xiaoling ; Zimmers, Teresa ; 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.
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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.",
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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

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

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.

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