TLR7/8/9 agonists and low-dose cisplatin synergistically promotes tertiary lymphatic structure formation and antitumor immunity
Abstract In situ vaccination (ISV) triggers antitumor immune responses using the patient’s own cancer antigens, yet limited neoantigen release hampers its efficacy. Our novel combination therapy involves low-dose local cisplatin followed by ISV with a TLR7/8/9 agonist formulation (CR108), in which C...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | npj Vaccines |
| Online Access: | https://doi.org/10.1038/s41541-024-01055-z |
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| author | Shuting Wu Rong Xiang Yiwei Zhong Shushu Zhao Zhiyu Zhang Zhihua Kou Shijie Zhang Yi Zhao Cheng Zu Gan Zhao Yanling Xiao Sulin Ren Xiaoming Gao Bin Wang |
| author_facet | Shuting Wu Rong Xiang Yiwei Zhong Shushu Zhao Zhiyu Zhang Zhihua Kou Shijie Zhang Yi Zhao Cheng Zu Gan Zhao Yanling Xiao Sulin Ren Xiaoming Gao Bin Wang |
| author_sort | Shuting Wu |
| collection | DOAJ |
| description | Abstract In situ vaccination (ISV) triggers antitumor immune responses using the patient’s own cancer antigens, yet limited neoantigen release hampers its efficacy. Our novel combination therapy involves low-dose local cisplatin followed by ISV with a TLR7/8/9 agonist formulation (CR108), in which CR108 boosts and sustains the antitumor responses induced by the cisplatin-released neoantigens. In mouse models, the cisplatin+CR108 combination significantly outperformed cisplatin or CR108 alone in abrogating established 4T1 and B16 tumors. The synergistic antitumor effects of cisplatin and CR108 were accompanied by markedly increased tumor tertiary lymphatic structures (TLS) formation, higher levels of type I and III interferons and TNF-α in serum, augmented T and B lymphocyte infiltration, antigen-presenting cell activation, as well as reduced functionally of exhausted T cells. Single-cell sequencing analysis uncovered a potential pathway for TLS to serve as a reservoir for functional antitumor effector T cells. Furthermore, cisplatin+CR108 combo therapy, but neither cisplatin nor CR108 alone, effectively inhibited the growth of treated 4T-1 tumor in an effector T cell-dependent manner. Notably, the combo therapy also suppressed the growth of distant untreated 4T-1 tumors, demonstrating systemic antitumor effects. Moreover, combo-therapy led to full regression of 4T-1 tumors in a large percentage of mice, who became strongly resistant to secondary tumor challenge, a clear indication of antitumor immunological memory. The cisplatin+CR108 combo therapy holds promise in converting “cold” tumors into “hot” ones and eliciting robust antitumor immune responses in vivo. |
| format | Article |
| id | doaj-art-595087b9476b4180b7fbce7a3940e44c |
| institution | Kabale University |
| issn | 2059-0105 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Vaccines |
| spelling | doaj-art-595087b9476b4180b7fbce7a3940e44c2025-01-19T12:09:21ZengNature Portfolionpj Vaccines2059-01052025-01-0110111210.1038/s41541-024-01055-zTLR7/8/9 agonists and low-dose cisplatin synergistically promotes tertiary lymphatic structure formation and antitumor immunityShuting Wu0Rong Xiang1Yiwei Zhong2Shushu Zhao3Zhiyu Zhang4Zhihua Kou5Shijie Zhang6Yi Zhao7Cheng Zu8Gan Zhao9Yanling Xiao10Sulin Ren11Xiaoming Gao12Bin Wang13Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan UniversityShanghai Institute of Infectious Disease and Biosecurity, Fudan UniversityKey Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan UniversityKey Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan UniversityAdvaccine Biopharmaceutics (Suzhou) Co. LTDAdvaccine Biopharmaceutics (Suzhou) Co. LTDAdvaccine Biopharmaceutics (Suzhou) Co. LTDPrecision Scientific (Beijing) LTD.Shanghai Institute of Infectious Disease and Biosecurity, Fudan UniversityAdvaccine Biopharmaceutics (Suzhou) Co. LTDAdvaccine Biopharmaceutics (Suzhou) Co. LTDAdvaccine Biopharmaceutics (Suzhou) Co. LTDAdvaccine Biopharmaceutics (Suzhou) Co. LTDKey Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan UniversityAbstract In situ vaccination (ISV) triggers antitumor immune responses using the patient’s own cancer antigens, yet limited neoantigen release hampers its efficacy. Our novel combination therapy involves low-dose local cisplatin followed by ISV with a TLR7/8/9 agonist formulation (CR108), in which CR108 boosts and sustains the antitumor responses induced by the cisplatin-released neoantigens. In mouse models, the cisplatin+CR108 combination significantly outperformed cisplatin or CR108 alone in abrogating established 4T1 and B16 tumors. The synergistic antitumor effects of cisplatin and CR108 were accompanied by markedly increased tumor tertiary lymphatic structures (TLS) formation, higher levels of type I and III interferons and TNF-α in serum, augmented T and B lymphocyte infiltration, antigen-presenting cell activation, as well as reduced functionally of exhausted T cells. Single-cell sequencing analysis uncovered a potential pathway for TLS to serve as a reservoir for functional antitumor effector T cells. Furthermore, cisplatin+CR108 combo therapy, but neither cisplatin nor CR108 alone, effectively inhibited the growth of treated 4T-1 tumor in an effector T cell-dependent manner. Notably, the combo therapy also suppressed the growth of distant untreated 4T-1 tumors, demonstrating systemic antitumor effects. Moreover, combo-therapy led to full regression of 4T-1 tumors in a large percentage of mice, who became strongly resistant to secondary tumor challenge, a clear indication of antitumor immunological memory. The cisplatin+CR108 combo therapy holds promise in converting “cold” tumors into “hot” ones and eliciting robust antitumor immune responses in vivo.https://doi.org/10.1038/s41541-024-01055-z |
| spellingShingle | Shuting Wu Rong Xiang Yiwei Zhong Shushu Zhao Zhiyu Zhang Zhihua Kou Shijie Zhang Yi Zhao Cheng Zu Gan Zhao Yanling Xiao Sulin Ren Xiaoming Gao Bin Wang TLR7/8/9 agonists and low-dose cisplatin synergistically promotes tertiary lymphatic structure formation and antitumor immunity npj Vaccines |
| title | TLR7/8/9 agonists and low-dose cisplatin synergistically promotes tertiary lymphatic structure formation and antitumor immunity |
| title_full | TLR7/8/9 agonists and low-dose cisplatin synergistically promotes tertiary lymphatic structure formation and antitumor immunity |
| title_fullStr | TLR7/8/9 agonists and low-dose cisplatin synergistically promotes tertiary lymphatic structure formation and antitumor immunity |
| title_full_unstemmed | TLR7/8/9 agonists and low-dose cisplatin synergistically promotes tertiary lymphatic structure formation and antitumor immunity |
| title_short | TLR7/8/9 agonists and low-dose cisplatin synergistically promotes tertiary lymphatic structure formation and antitumor immunity |
| title_sort | tlr7 8 9 agonists and low dose cisplatin synergistically promotes tertiary lymphatic structure formation and antitumor immunity |
| url | https://doi.org/10.1038/s41541-024-01055-z |
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