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

Publication Date:
2018-01-10
Publisher:
BMJ Publishing Group
Print ISSN:
0017-5749
Electronic ISSN:
1468-3288
Topics:
Medicine
Published by:
http://www.bmj.com/
_version_ 1836398742597533696
autor Mace, T. A., Shakya, R., Pitarresi, J. R., Swanson, B., McQuinn, C. W., Loftus, S., Nordquist, E., Cruz-Monserrate, Z., Yu, L., Young, G., Zhong, X., Zimmers, T. A., Ostrowski, M. C., Ludwig, T., Bloomston, M., Bekaii-Saab, T., Lesinski, G. B.
beschreibung 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 (Kras LSL–G12D , Trp53 LSL–R270H , Pdx1-cre, Brca2 F/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.
citation_standardnr 6134903
datenlieferant ipn_articles
feed_id 3103
feed_publisher BMJ Publishing Group
feed_publisher_url http://www.bmj.com/
insertion_date 2018-01-10
journaleissn 1468-3288
journalissn 0017-5749
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher BMJ Publishing Group
quelle Gut
relation http://gut.bmj.com/cgi/content/short/67/2/320?rss=1
search_space articles
shingle_author_1 Mace, T. A., Shakya, R., Pitarresi, J. R., Swanson, B., McQuinn, C. W., Loftus, S., Nordquist, E., Cruz-Monserrate, Z., Yu, L., Young, G., Zhong, X., Zimmers, T. A., Ostrowski, M. C., Ludwig, T., Bloomston, M., Bekaii-Saab, T., Lesinski, G. B.
shingle_author_2 Mace, T. A., Shakya, R., Pitarresi, J. R., Swanson, B., McQuinn, C. W., Loftus, S., Nordquist, E., Cruz-Monserrate, Z., Yu, L., Young, G., Zhong, X., Zimmers, T. A., Ostrowski, M. C., Ludwig, T., Bloomston, M., Bekaii-Saab, T., Lesinski, G. B.
shingle_author_3 Mace, T. A., Shakya, R., Pitarresi, J. R., Swanson, B., McQuinn, C. W., Loftus, S., Nordquist, E., Cruz-Monserrate, Z., Yu, L., Young, G., Zhong, X., Zimmers, T. A., Ostrowski, M. C., Ludwig, T., Bloomston, M., Bekaii-Saab, T., Lesinski, G. B.
shingle_author_4 Mace, T. A., Shakya, R., Pitarresi, J. R., Swanson, B., McQuinn, C. W., Loftus, S., Nordquist, E., Cruz-Monserrate, Z., Yu, L., Young, G., Zhong, X., Zimmers, T. A., Ostrowski, M. C., Ludwig, T., Bloomston, M., Bekaii-Saab, T., Lesinski, G. B.
shingle_catch_all_1 IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer
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 (Kras LSL–G12D , Trp53 LSL–R270H , Pdx1-cre, Brca2 F/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.
Mace, T. A., Shakya, R., Pitarresi, J. R., Swanson, B., McQuinn, C. W., Loftus, S., Nordquist, E., Cruz-Monserrate, Z., Yu, L., Young, G., Zhong, X., Zimmers, T. A., Ostrowski, M. C., Ludwig, T., Bloomston, M., Bekaii-Saab, T., Lesinski, G. B.
BMJ Publishing Group
0017-5749
00175749
1468-3288
14683288
shingle_catch_all_2 IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer
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 (Kras LSL–G12D , Trp53 LSL–R270H , Pdx1-cre, Brca2 F/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.
Mace, T. A., Shakya, R., Pitarresi, J. R., Swanson, B., McQuinn, C. W., Loftus, S., Nordquist, E., Cruz-Monserrate, Z., Yu, L., Young, G., Zhong, X., Zimmers, T. A., Ostrowski, M. C., Ludwig, T., Bloomston, M., Bekaii-Saab, T., Lesinski, G. B.
BMJ Publishing Group
0017-5749
00175749
1468-3288
14683288
shingle_catch_all_3 IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer
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 (Kras LSL–G12D , Trp53 LSL–R270H , Pdx1-cre, Brca2 F/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.
Mace, T. A., Shakya, R., Pitarresi, J. R., Swanson, B., McQuinn, C. W., Loftus, S., Nordquist, E., Cruz-Monserrate, Z., Yu, L., Young, G., Zhong, X., Zimmers, T. A., Ostrowski, M. C., Ludwig, T., Bloomston, M., Bekaii-Saab, T., Lesinski, G. B.
BMJ Publishing Group
0017-5749
00175749
1468-3288
14683288
shingle_catch_all_4 IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer
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 (Kras LSL–G12D , Trp53 LSL–R270H , Pdx1-cre, Brca2 F/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.
Mace, T. A., Shakya, R., Pitarresi, J. R., Swanson, B., McQuinn, C. W., Loftus, S., Nordquist, E., Cruz-Monserrate, Z., Yu, L., Young, G., Zhong, X., Zimmers, T. A., Ostrowski, M. C., Ludwig, T., Bloomston, M., Bekaii-Saab, T., Lesinski, G. B.
BMJ Publishing Group
0017-5749
00175749
1468-3288
14683288
shingle_title_1 IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer
shingle_title_2 IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer
shingle_title_3 IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer
shingle_title_4 IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer
timestamp 2025-06-30T23:31:55.419Z
titel IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer
titel_suche IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer
topic WW-YZ
uid ipn_articles_6134903