Tumor epitope spreading by a novel multivalent therapeutic cellular vaccine targeting cancer antigens to invariant NKT-triggered dendritic cells in situ
IntroductionCancer is categorized into two types based on the microenvironment: cold and hot tumors. The former is challenging to stimulate through immunity. The immunogenicity of cancer relies on the quality and quantity of cancer antigens, whether recognized by T cells or not. Successful cancer im...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1345037/full |
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| author | Satoru Yamasaki Kanako Shimizu Kanako Shimizu Shin-ichiro Fujii Shin-ichiro Fujii Shin-ichiro Fujii |
| author_facet | Satoru Yamasaki Kanako Shimizu Kanako Shimizu Shin-ichiro Fujii Shin-ichiro Fujii Shin-ichiro Fujii |
| author_sort | Satoru Yamasaki |
| collection | DOAJ |
| description | IntroductionCancer is categorized into two types based on the microenvironment: cold and hot tumors. The former is challenging to stimulate through immunity. The immunogenicity of cancer relies on the quality and quantity of cancer antigens, whether recognized by T cells or not. Successful cancer immunotherapy hinges on the cancer cell type, antigenicity and subsequent immune reactions. The T cell response is particularly crucial for secondary epitope spreading, although the factors affecting these mechanisms remain unknown. Prostate cancer often becomes resistant to standard therapy despite identifying several antigens, placing it among immunologically cold tumors. We aim to leverage prostate cancer antigens to investigate the potential induction of epitope spreading in cold tumors. This study specifically focuses on identifying factors involved in secondary epitope spreading based on artificial adjuvant vector cell (aAVC) therapy, a method established as invariant natural killer T (iNKT) -licensed DC therapy.MethodsWe concentrated on three prostate cancer antigens (prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP)). By introducing allogeneic cells with the antigen and murine CD1d mRNA, followed by α-galactosylceramide (α-GalCer) loading, we generated five types of aAVCs, i.e, monovalent, divalent and trivalent antigen-expressing aAVCs and four types of prostate antigen-expressing cold tumors. We evaluated iNKT activation and antigen-specific CD8+ T cell responses against tumor cells prompted by the aAVCs.ResultsOur study revealed that monovalent aAVCs, expressing a single prostate antigen, primed T cells for primary tumor antigens and also induced T cells targeting additional tumor antigens by triggering a tumor antigen-spreading response. When we investigated the immune response by trivalent aAVC (aAVC-PROS), aAVC-PROS therapy elicited multiple antigen-specific CD8+ T cells simultaneously. These CD8+ T cells exhibited both preventive and therapeutic effects against tumor progression.ConclusionsThe findings from this study highlight the promising role of tumor antigen-expressing aAVCs, in inducing efficient epitope spreading and generating robust immune responses against cancer. Our results also propose that multivalent antigen-expressing aAVCs present a promising therapeutic option and could be a more comprehensive therapy for treating cold tumors like prostate cancer. |
| first_indexed | 2024-03-08T08:51:30Z |
| format | Article |
| id | doaj.art-a2f1b2a265e349ac9661ed7a92fc051a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-08T08:51:30Z |
| publishDate | 2024-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-a2f1b2a265e349ac9661ed7a92fc051a2024-02-01T08:56:50ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-02-011510.3389/fimmu.2024.13450371345037Tumor epitope spreading by a novel multivalent therapeutic cellular vaccine targeting cancer antigens to invariant NKT-triggered dendritic cells in situSatoru Yamasaki0Kanako Shimizu1Kanako Shimizu2Shin-ichiro Fujii3Shin-ichiro Fujii4Shin-ichiro Fujii5Laboratory for Immunotherapy, RIKEN Research Center for Integrative Medical Science (IMS), Yokohama, JapanLaboratory for Immunotherapy, RIKEN Research Center for Integrative Medical Science (IMS), Yokohama, JapanaAVC Drug Translational Unit, RIKEN Center for Integrative Medical Science (IMS), Yokohama, JapanLaboratory for Immunotherapy, RIKEN Research Center for Integrative Medical Science (IMS), Yokohama, JapanaAVC Drug Translational Unit, RIKEN Center for Integrative Medical Science (IMS), Yokohama, JapanRIKEN Program for Drug Discovery and Medical Technology Platforms, Yokohama, JapanIntroductionCancer is categorized into two types based on the microenvironment: cold and hot tumors. The former is challenging to stimulate through immunity. The immunogenicity of cancer relies on the quality and quantity of cancer antigens, whether recognized by T cells or not. Successful cancer immunotherapy hinges on the cancer cell type, antigenicity and subsequent immune reactions. The T cell response is particularly crucial for secondary epitope spreading, although the factors affecting these mechanisms remain unknown. Prostate cancer often becomes resistant to standard therapy despite identifying several antigens, placing it among immunologically cold tumors. We aim to leverage prostate cancer antigens to investigate the potential induction of epitope spreading in cold tumors. This study specifically focuses on identifying factors involved in secondary epitope spreading based on artificial adjuvant vector cell (aAVC) therapy, a method established as invariant natural killer T (iNKT) -licensed DC therapy.MethodsWe concentrated on three prostate cancer antigens (prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP)). By introducing allogeneic cells with the antigen and murine CD1d mRNA, followed by α-galactosylceramide (α-GalCer) loading, we generated five types of aAVCs, i.e, monovalent, divalent and trivalent antigen-expressing aAVCs and four types of prostate antigen-expressing cold tumors. We evaluated iNKT activation and antigen-specific CD8+ T cell responses against tumor cells prompted by the aAVCs.ResultsOur study revealed that monovalent aAVCs, expressing a single prostate antigen, primed T cells for primary tumor antigens and also induced T cells targeting additional tumor antigens by triggering a tumor antigen-spreading response. When we investigated the immune response by trivalent aAVC (aAVC-PROS), aAVC-PROS therapy elicited multiple antigen-specific CD8+ T cells simultaneously. These CD8+ T cells exhibited both preventive and therapeutic effects against tumor progression.ConclusionsThe findings from this study highlight the promising role of tumor antigen-expressing aAVCs, in inducing efficient epitope spreading and generating robust immune responses against cancer. Our results also propose that multivalent antigen-expressing aAVCs present a promising therapeutic option and could be a more comprehensive therapy for treating cold tumors like prostate cancer.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1345037/fullcancercytotoxic T celldendritic cellimmunotherapyiNKT cell |
| spellingShingle | Satoru Yamasaki Kanako Shimizu Kanako Shimizu Shin-ichiro Fujii Shin-ichiro Fujii Shin-ichiro Fujii Tumor epitope spreading by a novel multivalent therapeutic cellular vaccine targeting cancer antigens to invariant NKT-triggered dendritic cells in situ Frontiers in Immunology cancer cytotoxic T cell dendritic cell immunotherapy iNKT cell |
| title | Tumor epitope spreading by a novel multivalent therapeutic cellular vaccine targeting cancer antigens to invariant NKT-triggered dendritic cells in situ |
| title_full | Tumor epitope spreading by a novel multivalent therapeutic cellular vaccine targeting cancer antigens to invariant NKT-triggered dendritic cells in situ |
| title_fullStr | Tumor epitope spreading by a novel multivalent therapeutic cellular vaccine targeting cancer antigens to invariant NKT-triggered dendritic cells in situ |
| title_full_unstemmed | Tumor epitope spreading by a novel multivalent therapeutic cellular vaccine targeting cancer antigens to invariant NKT-triggered dendritic cells in situ |
| title_short | Tumor epitope spreading by a novel multivalent therapeutic cellular vaccine targeting cancer antigens to invariant NKT-triggered dendritic cells in situ |
| title_sort | tumor epitope spreading by a novel multivalent therapeutic cellular vaccine targeting cancer antigens to invariant nkt triggered dendritic cells in situ |
| topic | cancer cytotoxic T cell dendritic cell immunotherapy iNKT cell |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1345037/full |
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