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Preprint
Caerin 1.1 and 1.9 peptides halt B16 melanoma metastatic tumours via expanding cDC1 and reprogramming tumour macrophages
Research Square, Vol.10 August 2024
Research Square Company
2024
Abstract
Background
Cancer immunotherapy, particularly immune checkpoint inhibitors (ICBs) such as anti-PD-1 antibodies, has revolutionized cancer treatment, although response rates vary among patients. Previous studies have demonstrated that caerin 1.1 and 1.9, host-defence peptides from the Australian tree frog, enhance the effectiveness of anti-PD-1 and therapeutic vaccines in a murine TC-1 model by activating tumour-associated macrophages intratumorally.
Methods
We employed a murine B16 melanoma model to investigate the therapeutic potential of caerin 1.1 and 1.9 in combination with anti-CD47 and a therapeutic vaccine (triple therapy, TT). Tumour growth of caerin-injected primary tumours and distant metastatic tumours was assessed, and survival analysis conducted. Single-cell RNA sequencing (scRNAseq) of CD45+ cells isolated from distant tumours was performed to elucidate changes in the tumour microenvironment induced by TT.
Results
The TT treatment significantly reduced tumour volumes on the treated side compared to untreated and control groups, with notable effects observed by Day 21. Survival analysis indicated extended survival in mice receiving TT, both on the treated and distant sides. scRNAseq revealed a notable expansion of conventional type 1 dendritic cells (cDC1s) and CD4+CD8+ T cells in the TT group. Tumour-associated macrophages in the TT group shifted toward a more immune-responsive M1 phenotype, with enhanced communication observed between cDC1s and CD8+ and CD4+CD25+ T cells. Additionally, TT downregulated M2-like macrophage marker genes, particularly in MHCIIhi and tissue-resident macrophages, suppressing Cd68 and Arg1 expression across all macrophage types. Differential gene expression analysis highlighted pathway alterations, including upregulation of oxidative phosphorylation and MYC target V1 in Arg1hi macrophages, and activation of pro-inflammatory pathways in MHCIIhi and tissue-resident macrophages.
Conclusion
Our findings suggest that caerin 1.1 and 1.9, combined with immunotherapy, effectively modulate the tumour microenvironment in primary and secondary tumours, leading to reduced tumour growth and enhanced systemic immunity. Further investigation into these mechanisms could pave the way for improved combination therapies in advanced melanoma treatment.
Details
- Title
- Caerin 1.1 and 1.9 peptides halt B16 melanoma metastatic tumours via expanding cDC1 and reprogramming tumour macrophages
- Authors
- Quanlan Fu (Author) - Guizhou UniversityYuandong Luo (Author) - First People's Hospital of FoshanJunjie Li (Author) - Zhongao Bio-pharmaceutical Technology Co., Ltd. (China)Hejie Li (Author) - University of the Sunshine Coast, Queensland, School of Science, Technology and EngineeringXiaosong Liu (Author) - First People's Hospital of FoshanZhu Chen (Author) - Guiyang Medical UniversityGuoying Ni (Author) - First People's Hospital of FoshanTianfang Wang (Corresponding Author) - University of the Sunshine Coast, Queensland, Centre for Bioinnovation
- Publication details
- Research Square, Vol.10 August 2024
- Publisher
- Research Square Company
- Date published
- 2024
- DOI
- 10.21203/rs.3.rs-4671312/v1
- ISSN
- 2693-5015
- Copyright note
- This work is licensed under a CC BY 4.0 License.
- Data Availability
- The scRNAseq dataset presented in this study can be found in online repository: https://singlecell.broadinstitute.org/single_cell, SCP2697.
- Grant note
- This study was supported in part by the First Affiliated Hospital of Guangdong Pharmaceutical University, Deng Feng project of Foshan First People’s Hospital (2019A008), National Science Foundation of Guangdong province (2020A1515010855), National Natural Science Foundation of China (31971355).
- Organisation Unit
- School of Science and Engineering - Legacy; GeneCology Research Centre - Legacy; School of Science, Technology and Engineering; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 991061498502621
- Output Type
- Preprint
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