Caerin 1.1/1.9-mediated antitumor immunity depends on IFNAR-Stat1 signalling of tumour infiltrating macrophage by autocrine IFNα and is enhanced by CD47 blockade
Abstract Previously, we demonstrated that natural host-defence peptide caerin 1.1/caerin 1.9 (F1/F3) increases the efficacy of anti-PD-1 and therapeutic vaccine, in a HPV16 + TC-1 tumour model, but the anti-tumor mechanism of F1/F3 is still unclear. In this study, we explored the impact of F1/F3 on...
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Nature Portfolio
2025-01-01
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| author | Junjie Li Yuandong Luo Quanlan Fu Shuxian Tang Pingping Zhang Ian H. Frazer Xiaosong Liu Tianfang Wang Guoying Ni |
| author_facet | Junjie Li Yuandong Luo Quanlan Fu Shuxian Tang Pingping Zhang Ian H. Frazer Xiaosong Liu Tianfang Wang Guoying Ni |
| author_sort | Junjie Li |
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| description | Abstract Previously, we demonstrated that natural host-defence peptide caerin 1.1/caerin 1.9 (F1/F3) increases the efficacy of anti-PD-1 and therapeutic vaccine, in a HPV16 + TC-1 tumour model, but the anti-tumor mechanism of F1/F3 is still unclear. In this study, we explored the impact of F1/F3 on the tumor microenvironment in a transplanted B16 melanoma model, and further investigated the mechanism of action of F1/F3 using monoclonal antibodies to deplete relevant cells, gene knockout mice and flow cytometry. We show that F1/F3 is able to inhibit the growth of melanoma B16 tumour cells both in vitro and in vivo. Depletion of macrophages, blockade of IFNα receptor, and Stat1 inhibition each abolishes F1/F3-mediated antitumor responses. Subsequent analysis reveals that F1/F3 increases the tumour infiltration of inflammatory macrophages, upregulates the level of IFNα receptor, and promotes the secretion of IFNα by macrophages. Interestingly, F1/F3 upregulates CD47 level on tumour cells; and blocking CD47 increases F1/F3-mediated antitumor responses. Furthermore, F1/F3 intratumor injection, CD47 blockade, and therapeutic vaccination significantly increases the survival time of B16 tumour-bearing mice. These results indicate that F1/F3 may be effective to improve the efficacy of ICB and therapeutic vaccine-based immunotherapy for human epithelial cancers and warrants consideration for clinical trials. |
| format | Article |
| id | doaj-art-6f205823ad9d4e8f94420fd204a39255 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-6f205823ad9d4e8f94420fd204a392552025-02-02T12:15:52ZengNature PortfolioScientific Reports2045-23222025-01-0115111710.1038/s41598-025-87687-0Caerin 1.1/1.9-mediated antitumor immunity depends on IFNAR-Stat1 signalling of tumour infiltrating macrophage by autocrine IFNα and is enhanced by CD47 blockadeJunjie Li0Yuandong Luo1Quanlan Fu2Shuxian Tang3Pingping Zhang4Ian H. Frazer5Xiaosong Liu6Tianfang Wang7Guoying Ni8Key Laboratory of Cancer Immunotherapy of Guangdong Tertiary Education, Guangdong CAR-T Treatment Related Adverse Reaction Key Laboratory, The First Affiliated Hospital/Clinical Medical School, Guangdong Pharmaceutical UniversityMedical School of Guizhou UniversityMedical School of Guizhou UniversityCancer Research Institute, Foshan First People’s HospitalCancer Research Institute, Foshan First People’s HospitalDiamantia Institute, Translational Research Institute, University of QueenslandKey Laboratory of Cancer Immunotherapy of Guangdong Tertiary Education, Guangdong CAR-T Treatment Related Adverse Reaction Key Laboratory, The First Affiliated Hospital/Clinical Medical School, Guangdong Pharmaceutical UniversityCentre for Bioinnovation, University of the Sunshine CoastKey Laboratory of Cancer Immunotherapy of Guangdong Tertiary Education, Guangdong CAR-T Treatment Related Adverse Reaction Key Laboratory, The First Affiliated Hospital/Clinical Medical School, Guangdong Pharmaceutical UniversityAbstract Previously, we demonstrated that natural host-defence peptide caerin 1.1/caerin 1.9 (F1/F3) increases the efficacy of anti-PD-1 and therapeutic vaccine, in a HPV16 + TC-1 tumour model, but the anti-tumor mechanism of F1/F3 is still unclear. In this study, we explored the impact of F1/F3 on the tumor microenvironment in a transplanted B16 melanoma model, and further investigated the mechanism of action of F1/F3 using monoclonal antibodies to deplete relevant cells, gene knockout mice and flow cytometry. We show that F1/F3 is able to inhibit the growth of melanoma B16 tumour cells both in vitro and in vivo. Depletion of macrophages, blockade of IFNα receptor, and Stat1 inhibition each abolishes F1/F3-mediated antitumor responses. Subsequent analysis reveals that F1/F3 increases the tumour infiltration of inflammatory macrophages, upregulates the level of IFNα receptor, and promotes the secretion of IFNα by macrophages. Interestingly, F1/F3 upregulates CD47 level on tumour cells; and blocking CD47 increases F1/F3-mediated antitumor responses. Furthermore, F1/F3 intratumor injection, CD47 blockade, and therapeutic vaccination significantly increases the survival time of B16 tumour-bearing mice. These results indicate that F1/F3 may be effective to improve the efficacy of ICB and therapeutic vaccine-based immunotherapy for human epithelial cancers and warrants consideration for clinical trials.https://doi.org/10.1038/s41598-025-87687-0Caerin 1.1/1.9IFNAR-1/STAT1α-PD-1Anti-CD47 |
| spellingShingle | Junjie Li Yuandong Luo Quanlan Fu Shuxian Tang Pingping Zhang Ian H. Frazer Xiaosong Liu Tianfang Wang Guoying Ni Caerin 1.1/1.9-mediated antitumor immunity depends on IFNAR-Stat1 signalling of tumour infiltrating macrophage by autocrine IFNα and is enhanced by CD47 blockade Scientific Reports Caerin 1.1/1.9 IFNAR-1/STAT1 α-PD-1 Anti-CD47 |
| title | Caerin 1.1/1.9-mediated antitumor immunity depends on IFNAR-Stat1 signalling of tumour infiltrating macrophage by autocrine IFNα and is enhanced by CD47 blockade |
| title_full | Caerin 1.1/1.9-mediated antitumor immunity depends on IFNAR-Stat1 signalling of tumour infiltrating macrophage by autocrine IFNα and is enhanced by CD47 blockade |
| title_fullStr | Caerin 1.1/1.9-mediated antitumor immunity depends on IFNAR-Stat1 signalling of tumour infiltrating macrophage by autocrine IFNα and is enhanced by CD47 blockade |
| title_full_unstemmed | Caerin 1.1/1.9-mediated antitumor immunity depends on IFNAR-Stat1 signalling of tumour infiltrating macrophage by autocrine IFNα and is enhanced by CD47 blockade |
| title_short | Caerin 1.1/1.9-mediated antitumor immunity depends on IFNAR-Stat1 signalling of tumour infiltrating macrophage by autocrine IFNα and is enhanced by CD47 blockade |
| title_sort | caerin 1 1 1 9 mediated antitumor immunity depends on ifnar stat1 signalling of tumour infiltrating macrophage by autocrine ifnα and is enhanced by cd47 blockade |
| topic | Caerin 1.1/1.9 IFNAR-1/STAT1 α-PD-1 Anti-CD47 |
| url | https://doi.org/10.1038/s41598-025-87687-0 |
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