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Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer

BACKGROUND: The pancreatic cancer vaccine, GVAX, induces novel lymphoid aggregates in the otherwise immune quiescent pancreatic ductal adenocarcinoma (PDAC). GVAX also upregulates the PD-1/PD-L1 pathway, and a pre-clinical model demonstrated the anti-tumor effects of combination GVAX and anti-PD-1 a...

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Autores principales: Saung, May Tun, Muth, Stephen, Ding, Ding, Thomas, Dwayne L., Blair, Alex B., Tsujikawa, Takahiro, Coussens, Lisa, Jaffee, Elizabeth M., Zheng, Lei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234697/
https://www.ncbi.nlm.nih.gov/pubmed/30424804
http://dx.doi.org/10.1186/s40425-018-0435-6
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author Saung, May Tun
Muth, Stephen
Ding, Ding
Thomas, Dwayne L.
Blair, Alex B.
Tsujikawa, Takahiro
Coussens, Lisa
Jaffee, Elizabeth M.
Zheng, Lei
author_facet Saung, May Tun
Muth, Stephen
Ding, Ding
Thomas, Dwayne L.
Blair, Alex B.
Tsujikawa, Takahiro
Coussens, Lisa
Jaffee, Elizabeth M.
Zheng, Lei
author_sort Saung, May Tun
collection PubMed
description BACKGROUND: The pancreatic cancer vaccine, GVAX, induces novel lymphoid aggregates in the otherwise immune quiescent pancreatic ductal adenocarcinoma (PDAC). GVAX also upregulates the PD-1/PD-L1 pathway, and a pre-clinical model demonstrated the anti-tumor effects of combination GVAX and anti-PD-1 antibody therapy (GVAX/αPD-1). Resistance to GVAX was associated with an immune-suppressive myeloid cell infiltration, which may limit further therapeutic gains of GVAX/αPD-1 therapy. The expression of CSF-1R, a receptor important for myeloid cell migration, differentiation and survival, and the effect of its therapeutic blockade in the context of GVAX in PDAC has not been investigated. METHODS: Lymphoid aggregates appreciated in 24 surgically resected PDAC from patients who received one dose of neoadjuvant GVAX were analyzed with multiplex immunohistochemistry. Flow cytometry analysis of tumor infiltrating T-cells in a murine model of PDAC was performed to investigate the therapeutic effects and mechanism of anti-CSF-1R/anti-PD-1/GVAX combination immunotherapy. RESULTS: High CSF-1R expression in resected PDAC from patients who received neoadjuvant GVAX was associated with a higher myeloid to lymphoid cell ratio (p < 0.05), which has been associated with poorer survival. This higher CSF-1R expression was associated with a higher intra-tumoral infiltration of immature dendritic cells (p < 0.05), but not mature dendritic cells (p = 0.132). In the pre-clinical murine model, administering anti-CSF-1R antibody prior to and after GVAX/αPD-1 (“pre/post-αCSF-1R + αPD-1 + GVAX”) enhanced the survival rate compared to GVAX/αPD-1 dual therapy (p = 0.005), but administering anti-CSF-1R only before GVAX/αPD-1 did not (p = 0.41). The “pre/post-αCSF-1R + αPD-1 + GVAX” group also had higher intra-tumoral infiltration of PD-1 + CD8+ and PD-1 + CD4+ T-cells compared to αPD-1/GVAX (p < 0.001). Furthermore, this regimen increased the intra-tumoral infiltration of PD-1 + CD137 + CD8+, PD-1 + CD137 + CD4+ and PD-1 + OX40 + CD4+ T-cells (p < 0.001). These PD-1 + CD137 + CD8+ T-cells expressed high levels of interferon-γ (median 80–90%) in response to stimulation with CD3/CD28 activation beads, and this expression was higher than that of PD-1 + CD137-CD8+ T-cells (p < 0.001). CONCLUSIONS: The conversion of exhausted PD-1+ T-cells to CD137+ activated effector T-cells may contribute to the anti-tumor effects of the anti-CSF-1R/anti-PD-1/GVAX combination therapy. Anti-CSF-1R antibody with anti-PD-1 antibody and GVAX have the potential be an effective therapeutic strategy for treatment of PDAC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40425-018-0435-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-62346972018-11-20 Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer Saung, May Tun Muth, Stephen Ding, Ding Thomas, Dwayne L. Blair, Alex B. Tsujikawa, Takahiro Coussens, Lisa Jaffee, Elizabeth M. Zheng, Lei J Immunother Cancer Research Article BACKGROUND: The pancreatic cancer vaccine, GVAX, induces novel lymphoid aggregates in the otherwise immune quiescent pancreatic ductal adenocarcinoma (PDAC). GVAX also upregulates the PD-1/PD-L1 pathway, and a pre-clinical model demonstrated the anti-tumor effects of combination GVAX and anti-PD-1 antibody therapy (GVAX/αPD-1). Resistance to GVAX was associated with an immune-suppressive myeloid cell infiltration, which may limit further therapeutic gains of GVAX/αPD-1 therapy. The expression of CSF-1R, a receptor important for myeloid cell migration, differentiation and survival, and the effect of its therapeutic blockade in the context of GVAX in PDAC has not been investigated. METHODS: Lymphoid aggregates appreciated in 24 surgically resected PDAC from patients who received one dose of neoadjuvant GVAX were analyzed with multiplex immunohistochemistry. Flow cytometry analysis of tumor infiltrating T-cells in a murine model of PDAC was performed to investigate the therapeutic effects and mechanism of anti-CSF-1R/anti-PD-1/GVAX combination immunotherapy. RESULTS: High CSF-1R expression in resected PDAC from patients who received neoadjuvant GVAX was associated with a higher myeloid to lymphoid cell ratio (p < 0.05), which has been associated with poorer survival. This higher CSF-1R expression was associated with a higher intra-tumoral infiltration of immature dendritic cells (p < 0.05), but not mature dendritic cells (p = 0.132). In the pre-clinical murine model, administering anti-CSF-1R antibody prior to and after GVAX/αPD-1 (“pre/post-αCSF-1R + αPD-1 + GVAX”) enhanced the survival rate compared to GVAX/αPD-1 dual therapy (p = 0.005), but administering anti-CSF-1R only before GVAX/αPD-1 did not (p = 0.41). The “pre/post-αCSF-1R + αPD-1 + GVAX” group also had higher intra-tumoral infiltration of PD-1 + CD8+ and PD-1 + CD4+ T-cells compared to αPD-1/GVAX (p < 0.001). Furthermore, this regimen increased the intra-tumoral infiltration of PD-1 + CD137 + CD8+, PD-1 + CD137 + CD4+ and PD-1 + OX40 + CD4+ T-cells (p < 0.001). These PD-1 + CD137 + CD8+ T-cells expressed high levels of interferon-γ (median 80–90%) in response to stimulation with CD3/CD28 activation beads, and this expression was higher than that of PD-1 + CD137-CD8+ T-cells (p < 0.001). CONCLUSIONS: The conversion of exhausted PD-1+ T-cells to CD137+ activated effector T-cells may contribute to the anti-tumor effects of the anti-CSF-1R/anti-PD-1/GVAX combination therapy. Anti-CSF-1R antibody with anti-PD-1 antibody and GVAX have the potential be an effective therapeutic strategy for treatment of PDAC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40425-018-0435-6) contains supplementary material, which is available to authorized users. BioMed Central 2018-11-13 /pmc/articles/PMC6234697/ /pubmed/30424804 http://dx.doi.org/10.1186/s40425-018-0435-6 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Saung, May Tun
Muth, Stephen
Ding, Ding
Thomas, Dwayne L.
Blair, Alex B.
Tsujikawa, Takahiro
Coussens, Lisa
Jaffee, Elizabeth M.
Zheng, Lei
Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer
title Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer
title_full Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer
title_fullStr Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer
title_full_unstemmed Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer
title_short Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer
title_sort targeting myeloid-inflamed tumor with anti-csf-1r antibody expands cd137+ effector t-cells in the murine model of pancreatic cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234697/
https://www.ncbi.nlm.nih.gov/pubmed/30424804
http://dx.doi.org/10.1186/s40425-018-0435-6
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