Nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in mice
Background Treatments for pancreatic ductal adenocarcinoma are poorly effective, at least partly due to the tumor’s immune-suppressive stromal compartment. New evidence of positive effects on immune responses in the tumor microenvironment (TME), compelled us to test the combination of gemcitabine (G...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e001250.full |
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| author | Ilse Rooman Claudia Gravekamp Lydie Meheus Amanda Beck Benson Chellakkan Selvanesan Kiran Meena Olaya Lara |
| author_facet | Ilse Rooman Claudia Gravekamp Lydie Meheus Amanda Beck Benson Chellakkan Selvanesan Kiran Meena Olaya Lara |
| author_sort | Ilse Rooman |
| collection | DOAJ |
| description | Background Treatments for pancreatic ductal adenocarcinoma are poorly effective, at least partly due to the tumor’s immune-suppressive stromal compartment. New evidence of positive effects on immune responses in the tumor microenvironment (TME), compelled us to test the combination of gemcitabine (GEM), a standard chemotherapeutic for pancreatic cancer, with nicotinamide (NAM), the amide form of niacin (vitamin B3), in mice with pancreatic cancer.Methods Various mouse tumor models of pancreatic cancer, that is, orthotopic Panc-02 and KPC (KrasG12D, p53R172H, Pdx1-Cre) grafts, were treated alternately with NAM and GEM for 2 weeks, and the effects on efficacy, survival, stromal architecture and tumor-infiltrating immune cells was examined by immunohistochemistry (IHC), flow cytometry, Enzyme-linked immunospot (ELISPOT), T cell depletions in vivo, Nanostring analysis and RNAscope.Results A significant reduction in tumor weight and number of metastases was found, as well as a significant improved survival of the NAM+GEM group compared with all control groups. IHC and flow cytometry showed a significant decrease in tumor-associated macrophages and myeloid-derived suppressor cells in the tumors of NAM+GEM-treated mice. This correlated with a significant increase in the number of CD4 and CD8 T cells of NAM+GEM-treated tumors, and CD4 and CD8 T cell responses to tumor-associated antigen survivin, most likely through epitope spreading. In vivo depletions of T cells demonstrated the involvement of CD4 T cells in the eradication of the tumor by NAM+GEM treatment. In addition, remodeling of the tumor stroma was observed with decreased collagen I and lower expression of hyaluronic acid binding protein, reorganization of the immune cells into lymph node like structures and CD31 positive vessels. Expression profiling for a panel of immuno-oncology genes revealed significant changes in genes involved in migration and activation of T cells, attraction of dendritic cells and epitope spreading.Conclusion This study highlights the potential of NAM+GEM as immunotherapy for advanced pancreatic cancer. |
| format | Article |
| id | doaj-art-a874e3fb0655429482879cb32148b701 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-a874e3fb0655429482879cb32148b7012024-11-11T02:25:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-001250Nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in miceIlse Rooman0Claudia Gravekamp1Lydie Meheus2Amanda Beck3Benson Chellakkan Selvanesan4Kiran Meena5Olaya Lara6Laboratory of Medical and Molecular Oncology, Vrije Universiteit Brussel, Brussel, BelgiumDepartment of Microbiology & Immunology, Albert Einstein College of Medicine, New York, New York, USAInnogenetics, Ghent, Belgium4 Department of Pharmacy, Houston Methodist Hospital, Houston, Texas, USA1 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA1 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA4 Laboratory of Medical and Molecular Oncology, Vrije Universiteit Brussel, Laarbeeklaan, Brussels, BelgiumBackground Treatments for pancreatic ductal adenocarcinoma are poorly effective, at least partly due to the tumor’s immune-suppressive stromal compartment. New evidence of positive effects on immune responses in the tumor microenvironment (TME), compelled us to test the combination of gemcitabine (GEM), a standard chemotherapeutic for pancreatic cancer, with nicotinamide (NAM), the amide form of niacin (vitamin B3), in mice with pancreatic cancer.Methods Various mouse tumor models of pancreatic cancer, that is, orthotopic Panc-02 and KPC (KrasG12D, p53R172H, Pdx1-Cre) grafts, were treated alternately with NAM and GEM for 2 weeks, and the effects on efficacy, survival, stromal architecture and tumor-infiltrating immune cells was examined by immunohistochemistry (IHC), flow cytometry, Enzyme-linked immunospot (ELISPOT), T cell depletions in vivo, Nanostring analysis and RNAscope.Results A significant reduction in tumor weight and number of metastases was found, as well as a significant improved survival of the NAM+GEM group compared with all control groups. IHC and flow cytometry showed a significant decrease in tumor-associated macrophages and myeloid-derived suppressor cells in the tumors of NAM+GEM-treated mice. This correlated with a significant increase in the number of CD4 and CD8 T cells of NAM+GEM-treated tumors, and CD4 and CD8 T cell responses to tumor-associated antigen survivin, most likely through epitope spreading. In vivo depletions of T cells demonstrated the involvement of CD4 T cells in the eradication of the tumor by NAM+GEM treatment. In addition, remodeling of the tumor stroma was observed with decreased collagen I and lower expression of hyaluronic acid binding protein, reorganization of the immune cells into lymph node like structures and CD31 positive vessels. Expression profiling for a panel of immuno-oncology genes revealed significant changes in genes involved in migration and activation of T cells, attraction of dendritic cells and epitope spreading.Conclusion This study highlights the potential of NAM+GEM as immunotherapy for advanced pancreatic cancer.https://jitc.bmj.com/content/8/2/e001250.full |
| spellingShingle | Ilse Rooman Claudia Gravekamp Lydie Meheus Amanda Beck Benson Chellakkan Selvanesan Kiran Meena Olaya Lara Nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in mice Journal for ImmunoTherapy of Cancer |
| title | Nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in mice |
| title_full | Nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in mice |
| title_fullStr | Nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in mice |
| title_full_unstemmed | Nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in mice |
| title_short | Nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in mice |
| title_sort | nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in mice |
| url | https://jitc.bmj.com/content/8/2/e001250.full |
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