Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma

Publication Date:
2018-05-09
Publisher:
BMJ Publishing Group
Print ISSN:
0017-5749
Electronic ISSN:
1468-3288
Topics:
Medicine
Keywords:
Open access, Gut
Published by:
http://www.bmj.com/
_version_ 1836398924951191552
autor Nywening, T. M., Belt, B. A., Cullinan, D. R., Panni, R. Z., Han, B. J., Sanford, D. E., Jacobs, R. C., Ye, J., Patel, A. A., Gillanders, W. E., Fields, R. C., De; Nardo, D. G., Hawkins, W. G., Goedegebuure, P., Linehan, D. C.
beschreibung Objective Chemokine pathways are co-opted by pancreatic adenocarcinoma (PDAC) to facilitate myeloid cell recruitment from the bone marrow to establish an immunosuppressive tumour microenvironment (TME). Targeting tumour-associated CXCR2 + neutrophils (TAN) or tumour-associated CCR2 + macrophages (TAM) alone improves antitumour immunity in preclinical models. However, a compensatory influx of an alternative myeloid subset may result in a persistent immunosuppressive TME and promote therapeutic resistance. Here, we show CCR2 and CXCR2 combined blockade reduces total tumour-infiltrating myeloids, promoting a more robust antitumour immune response in PDAC compared with either strategy alone. Methods Blood, bone marrow and tumours were analysed from PDAC patients and controls. Treatment response and correlative studies were performed in mice with established orthotopic PDAC tumours treated with a small molecule CCR2 inhibitor (CCR2i) and CXCR2 inhibitor (CXCR2i), alone and in combination with chemotherapy. Results A systemic increase in CXCR2 + TAN correlates with poor prognosis in PDAC, and patients receiving CCR2i showed increased tumour-infiltrating CXCR2 + TAN following treatment. In an orthotopic PDAC model, CXCR2 blockade prevented neutrophil mobilisation from the circulation and augmented chemotherapeutic efficacy. However, depletion of either CXCR2 + TAN or CCR2 + TAM resulted in a compensatory response of the alternative myeloid subset, recapitulating human disease. This was overcome by combined CCR2i and CXCR2i, which augmented antitumour immunity and improved response to FOLFIRINOX chemotherapy. Conclusion Dual targeting of CCR2 + TAM and CXCR2 + TAN improves antitumour immunity and chemotherapeutic response in PDAC compared with either strategy alone.
citation_standardnr 6253715
datenlieferant ipn_articles
feed_id 3103
feed_publisher BMJ Publishing Group
feed_publisher_url http://www.bmj.com/
insertion_date 2018-05-09
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/67/6/1112?rss=1
schlagwort Open access, Gut
search_space articles
shingle_author_1 Nywening, T. M., Belt, B. A., Cullinan, D. R., Panni, R. Z., Han, B. J., Sanford, D. E., Jacobs, R. C., Ye, J., Patel, A. A., Gillanders, W. E., Fields, R. C., De; Nardo, D. G., Hawkins, W. G., Goedegebuure, P., Linehan, D. C.
shingle_author_2 Nywening, T. M., Belt, B. A., Cullinan, D. R., Panni, R. Z., Han, B. J., Sanford, D. E., Jacobs, R. C., Ye, J., Patel, A. A., Gillanders, W. E., Fields, R. C., De; Nardo, D. G., Hawkins, W. G., Goedegebuure, P., Linehan, D. C.
shingle_author_3 Nywening, T. M., Belt, B. A., Cullinan, D. R., Panni, R. Z., Han, B. J., Sanford, D. E., Jacobs, R. C., Ye, J., Patel, A. A., Gillanders, W. E., Fields, R. C., De; Nardo, D. G., Hawkins, W. G., Goedegebuure, P., Linehan, D. C.
shingle_author_4 Nywening, T. M., Belt, B. A., Cullinan, D. R., Panni, R. Z., Han, B. J., Sanford, D. E., Jacobs, R. C., Ye, J., Patel, A. A., Gillanders, W. E., Fields, R. C., De; Nardo, D. G., Hawkins, W. G., Goedegebuure, P., Linehan, D. C.
shingle_catch_all_1 Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma
Open access, Gut
Objective Chemokine pathways are co-opted by pancreatic adenocarcinoma (PDAC) to facilitate myeloid cell recruitment from the bone marrow to establish an immunosuppressive tumour microenvironment (TME). Targeting tumour-associated CXCR2 + neutrophils (TAN) or tumour-associated CCR2 + macrophages (TAM) alone improves antitumour immunity in preclinical models. However, a compensatory influx of an alternative myeloid subset may result in a persistent immunosuppressive TME and promote therapeutic resistance. Here, we show CCR2 and CXCR2 combined blockade reduces total tumour-infiltrating myeloids, promoting a more robust antitumour immune response in PDAC compared with either strategy alone. Methods Blood, bone marrow and tumours were analysed from PDAC patients and controls. Treatment response and correlative studies were performed in mice with established orthotopic PDAC tumours treated with a small molecule CCR2 inhibitor (CCR2i) and CXCR2 inhibitor (CXCR2i), alone and in combination with chemotherapy. Results A systemic increase in CXCR2 + TAN correlates with poor prognosis in PDAC, and patients receiving CCR2i showed increased tumour-infiltrating CXCR2 + TAN following treatment. In an orthotopic PDAC model, CXCR2 blockade prevented neutrophil mobilisation from the circulation and augmented chemotherapeutic efficacy. However, depletion of either CXCR2 + TAN or CCR2 + TAM resulted in a compensatory response of the alternative myeloid subset, recapitulating human disease. This was overcome by combined CCR2i and CXCR2i, which augmented antitumour immunity and improved response to FOLFIRINOX chemotherapy. Conclusion Dual targeting of CCR2 + TAM and CXCR2 + TAN improves antitumour immunity and chemotherapeutic response in PDAC compared with either strategy alone.
Nywening, T. M., Belt, B. A., Cullinan, D. R., Panni, R. Z., Han, B. J., Sanford, D. E., Jacobs, R. C., Ye, J., Patel, A. A., Gillanders, W. E., Fields, R. C., De; Nardo, D. G., Hawkins, W. G., Goedegebuure, P., Linehan, D. C.
BMJ Publishing Group
0017-5749
00175749
1468-3288
14683288
shingle_catch_all_2 Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma
Open access, Gut
Objective Chemokine pathways are co-opted by pancreatic adenocarcinoma (PDAC) to facilitate myeloid cell recruitment from the bone marrow to establish an immunosuppressive tumour microenvironment (TME). Targeting tumour-associated CXCR2 + neutrophils (TAN) or tumour-associated CCR2 + macrophages (TAM) alone improves antitumour immunity in preclinical models. However, a compensatory influx of an alternative myeloid subset may result in a persistent immunosuppressive TME and promote therapeutic resistance. Here, we show CCR2 and CXCR2 combined blockade reduces total tumour-infiltrating myeloids, promoting a more robust antitumour immune response in PDAC compared with either strategy alone. Methods Blood, bone marrow and tumours were analysed from PDAC patients and controls. Treatment response and correlative studies were performed in mice with established orthotopic PDAC tumours treated with a small molecule CCR2 inhibitor (CCR2i) and CXCR2 inhibitor (CXCR2i), alone and in combination with chemotherapy. Results A systemic increase in CXCR2 + TAN correlates with poor prognosis in PDAC, and patients receiving CCR2i showed increased tumour-infiltrating CXCR2 + TAN following treatment. In an orthotopic PDAC model, CXCR2 blockade prevented neutrophil mobilisation from the circulation and augmented chemotherapeutic efficacy. However, depletion of either CXCR2 + TAN or CCR2 + TAM resulted in a compensatory response of the alternative myeloid subset, recapitulating human disease. This was overcome by combined CCR2i and CXCR2i, which augmented antitumour immunity and improved response to FOLFIRINOX chemotherapy. Conclusion Dual targeting of CCR2 + TAM and CXCR2 + TAN improves antitumour immunity and chemotherapeutic response in PDAC compared with either strategy alone.
Nywening, T. M., Belt, B. A., Cullinan, D. R., Panni, R. Z., Han, B. J., Sanford, D. E., Jacobs, R. C., Ye, J., Patel, A. A., Gillanders, W. E., Fields, R. C., De; Nardo, D. G., Hawkins, W. G., Goedegebuure, P., Linehan, D. C.
BMJ Publishing Group
0017-5749
00175749
1468-3288
14683288
shingle_catch_all_3 Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma
Open access, Gut
Objective Chemokine pathways are co-opted by pancreatic adenocarcinoma (PDAC) to facilitate myeloid cell recruitment from the bone marrow to establish an immunosuppressive tumour microenvironment (TME). Targeting tumour-associated CXCR2 + neutrophils (TAN) or tumour-associated CCR2 + macrophages (TAM) alone improves antitumour immunity in preclinical models. However, a compensatory influx of an alternative myeloid subset may result in a persistent immunosuppressive TME and promote therapeutic resistance. Here, we show CCR2 and CXCR2 combined blockade reduces total tumour-infiltrating myeloids, promoting a more robust antitumour immune response in PDAC compared with either strategy alone. Methods Blood, bone marrow and tumours were analysed from PDAC patients and controls. Treatment response and correlative studies were performed in mice with established orthotopic PDAC tumours treated with a small molecule CCR2 inhibitor (CCR2i) and CXCR2 inhibitor (CXCR2i), alone and in combination with chemotherapy. Results A systemic increase in CXCR2 + TAN correlates with poor prognosis in PDAC, and patients receiving CCR2i showed increased tumour-infiltrating CXCR2 + TAN following treatment. In an orthotopic PDAC model, CXCR2 blockade prevented neutrophil mobilisation from the circulation and augmented chemotherapeutic efficacy. However, depletion of either CXCR2 + TAN or CCR2 + TAM resulted in a compensatory response of the alternative myeloid subset, recapitulating human disease. This was overcome by combined CCR2i and CXCR2i, which augmented antitumour immunity and improved response to FOLFIRINOX chemotherapy. Conclusion Dual targeting of CCR2 + TAM and CXCR2 + TAN improves antitumour immunity and chemotherapeutic response in PDAC compared with either strategy alone.
Nywening, T. M., Belt, B. A., Cullinan, D. R., Panni, R. Z., Han, B. J., Sanford, D. E., Jacobs, R. C., Ye, J., Patel, A. A., Gillanders, W. E., Fields, R. C., De; Nardo, D. G., Hawkins, W. G., Goedegebuure, P., Linehan, D. C.
BMJ Publishing Group
0017-5749
00175749
1468-3288
14683288
shingle_catch_all_4 Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma
Open access, Gut
Objective Chemokine pathways are co-opted by pancreatic adenocarcinoma (PDAC) to facilitate myeloid cell recruitment from the bone marrow to establish an immunosuppressive tumour microenvironment (TME). Targeting tumour-associated CXCR2 + neutrophils (TAN) or tumour-associated CCR2 + macrophages (TAM) alone improves antitumour immunity in preclinical models. However, a compensatory influx of an alternative myeloid subset may result in a persistent immunosuppressive TME and promote therapeutic resistance. Here, we show CCR2 and CXCR2 combined blockade reduces total tumour-infiltrating myeloids, promoting a more robust antitumour immune response in PDAC compared with either strategy alone. Methods Blood, bone marrow and tumours were analysed from PDAC patients and controls. Treatment response and correlative studies were performed in mice with established orthotopic PDAC tumours treated with a small molecule CCR2 inhibitor (CCR2i) and CXCR2 inhibitor (CXCR2i), alone and in combination with chemotherapy. Results A systemic increase in CXCR2 + TAN correlates with poor prognosis in PDAC, and patients receiving CCR2i showed increased tumour-infiltrating CXCR2 + TAN following treatment. In an orthotopic PDAC model, CXCR2 blockade prevented neutrophil mobilisation from the circulation and augmented chemotherapeutic efficacy. However, depletion of either CXCR2 + TAN or CCR2 + TAM resulted in a compensatory response of the alternative myeloid subset, recapitulating human disease. This was overcome by combined CCR2i and CXCR2i, which augmented antitumour immunity and improved response to FOLFIRINOX chemotherapy. Conclusion Dual targeting of CCR2 + TAM and CXCR2 + TAN improves antitumour immunity and chemotherapeutic response in PDAC compared with either strategy alone.
Nywening, T. M., Belt, B. A., Cullinan, D. R., Panni, R. Z., Han, B. J., Sanford, D. E., Jacobs, R. C., Ye, J., Patel, A. A., Gillanders, W. E., Fields, R. C., De; Nardo, D. G., Hawkins, W. G., Goedegebuure, P., Linehan, D. C.
BMJ Publishing Group
0017-5749
00175749
1468-3288
14683288
shingle_title_1 Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma
shingle_title_2 Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma
shingle_title_3 Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma
shingle_title_4 Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma
timestamp 2025-06-30T23:34:46.134Z
titel Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma
titel_suche Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma
topic WW-YZ
uid ipn_articles_6253715