Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade
Background Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective i...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/11/e007661.full |
| _version_ | 1797435207700185088 |
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| author | Yan Luo Matthew S Block Barath Shreeder James W Jenkins Huashan Shi Purushottam Lamichhane Kexun Zhou Deborah A Bahr Sophia Kurian Katherine A Jones Joshua I Daum Navnita Dutta Brian M Necela Martin J Cannon Keith L Knutson |
| author_facet | Yan Luo Matthew S Block Barath Shreeder James W Jenkins Huashan Shi Purushottam Lamichhane Kexun Zhou Deborah A Bahr Sophia Kurian Katherine A Jones Joshua I Daum Navnita Dutta Brian M Necela Martin J Cannon Keith L Knutson |
| author_sort | Yan Luo |
| collection | DOAJ |
| description | Background Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing.Methods ID8 tumor cells were injected intraperitoneally into mice. Mice were treated with Th17-DC or conventional DC (cDC) vaccine alone or with immune checkpoint blockade (ICB). Systemic immunity, tumor associated immunity, tumor size and survival were examined using a variety of experimental strategies.Results Th17-DC vaccines increased Th17 T cells in the tumor microenvironment, reshaped the myeloid microenvironment, and improved mouse survival compared with cDC vaccines. ICB had limited efficacy in OC, but Th17-inducing DC vaccination sensitized it to anti-PD-1 ICB, resulting in durable progression-free survival by overcoming IL-10-mediated resistance. Th17-DC vaccine efficacy, alone or with ICB, was mediated by CD4 T cells, but not CD8 T cells.Conclusions These findings emphasize using biologically relevant immune modifiers, like Th17-DC vaccines, in OC treatment to reshape the tumor microenvironment and enhance clinical responses to ICB therapy. |
| first_indexed | 2024-03-09T10:43:55Z |
| format | Article |
| id | doaj.art-c7f089de207141e2ac20f5bd2a7c68ba |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-09T10:43:55Z |
| publishDate | 2023-11-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-c7f089de207141e2ac20f5bd2a7c68ba2023-12-01T11:40:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-11-01111110.1136/jitc-2023-007661Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockadeYan Luo0Matthew S Block1Barath Shreeder2James W Jenkins3Huashan Shi4Purushottam Lamichhane5Kexun Zhou6Deborah A Bahr7Sophia Kurian8Katherine A Jones9Joshua I Daum10Navnita Dutta11Brian M Necela12Martin J Cannon13Keith L Knutson14Department of Immunology, Mayo Clinic in Florida, Jacksonville, Florida, USADivison of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USADepartment of Immunology, Mayo Clinic in Florida, Jacksonville, Florida, USADepartment of Immunology, Mayo Clinic in Florida, Jacksonville, Florida, USADepartment of Immunology, Mayo Clinic in Florida, Jacksonville, Florida, USADepartment of Immunology, Mayo Clinic in Florida, Jacksonville, Florida, USADepartment of Immunology, Mayo Clinic in Florida, Jacksonville, Florida, USADepartment of Immunology, Mayo Clinic in Florida, Jacksonville, Florida, USADepartment of Immunology, Mayo Clinic in Florida, Jacksonville, Florida, USADepartment of Immunology, Mayo Clinic in Florida, Jacksonville, Florida, USADepartment of Immunology, Mayo Clinic in Florida, Jacksonville, Florida, USADepartment of Immunology, Mayo Clinic in Florida, Jacksonville, Florida, USADepartment of Immunology, Mayo Clinic in Florida, Jacksonville, Florida, USADepartment of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USADepartment of Immunology, Mayo Clinic in Florida, Jacksonville, Florida, USABackground Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing.Methods ID8 tumor cells were injected intraperitoneally into mice. Mice were treated with Th17-DC or conventional DC (cDC) vaccine alone or with immune checkpoint blockade (ICB). Systemic immunity, tumor associated immunity, tumor size and survival were examined using a variety of experimental strategies.Results Th17-DC vaccines increased Th17 T cells in the tumor microenvironment, reshaped the myeloid microenvironment, and improved mouse survival compared with cDC vaccines. ICB had limited efficacy in OC, but Th17-inducing DC vaccination sensitized it to anti-PD-1 ICB, resulting in durable progression-free survival by overcoming IL-10-mediated resistance. Th17-DC vaccine efficacy, alone or with ICB, was mediated by CD4 T cells, but not CD8 T cells.Conclusions These findings emphasize using biologically relevant immune modifiers, like Th17-DC vaccines, in OC treatment to reshape the tumor microenvironment and enhance clinical responses to ICB therapy.https://jitc.bmj.com/content/11/11/e007661.full |
| spellingShingle | Yan Luo Matthew S Block Barath Shreeder James W Jenkins Huashan Shi Purushottam Lamichhane Kexun Zhou Deborah A Bahr Sophia Kurian Katherine A Jones Joshua I Daum Navnita Dutta Brian M Necela Martin J Cannon Keith L Knutson Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade Journal for ImmunoTherapy of Cancer |
| title | Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade |
| title_full | Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade |
| title_fullStr | Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade |
| title_full_unstemmed | Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade |
| title_short | Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade |
| title_sort | th17 inducing dendritic cell vaccines stimulate effective cd4 t cell dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade |
| url | https://jitc.bmj.com/content/11/11/e007661.full |
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