Caerin 1.1 and 1.9 peptides halt B16 melanoma metastatic tumours via expanding cDC1 and reprogramming tumour macrophages

Quanlan Fu; Yuandong Luo; Junjie Li; Hejie Li; Xiaosong Liu; Zhu Chen; Guoying Ni; Tianfang Wang

doi:10.1186/s12967-024-05763-x

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Caerin 1.1 and 1.9 peptides halt B16 melanoma metastatic tumours via expanding cDC1 and reprogramming tumour macrophages

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Caerin 1.1 and 1.9 peptides halt B16 melanoma metastatic tumours via expanding cDC1 and reprogramming tumour macrophages

Quanlan Fu, Yuandong Luo, Junjie Li, Hejie Li, Xiaosong Liu, Zhu Chen, Guoying Ni and Tianfang Wang

Journal of Translational Medicine, Vol.22, pp.1-18

2024

DOI: https://doi.org/10.1186/s12967-024-05763-x

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Caerin 1.1 and 1.9 peptides halt B16 melanoma metastatic tumours via expanding c...

Abstract

caerin peptide

B16 cell

melanoma

macrophage

cDC1

CD4+CD8* T cell

cell-cell communication

anti-CD47 antibody

immunotherapy

Background Cancer immunotherapy, particularly immune checkpoint inhibitors (ICBs) such as anti-PD-1 antibodies, has revolutionised 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.

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Title: Caerin 1.1 and 1.9 peptides halt B16 melanoma metastatic tumours via expanding cDC1 and reprogramming tumour macrophages
Authors: Quanlan Fu - Guizhou University
Yuandong Luo - Guizhou University
Junjie Li - Guangdong Pharmaceutical University
Hejie Li - University of the Sunshine Coast, Queensland, School of Science, Technology and Engineering
Xiaosong Liu - First People's Hospital of Foshan
Zhu Chen (Corresponding Author) - Guiyang Stomatology Hospital (China)
Guoying Ni (Corresponding Author) - Guangdong Pharmaceutical University
Tianfang Wang (Corresponding Author) - University of the Sunshine Coast, Queensland, School of Science, Technology and Engineering
Publication details: Journal of Translational Medicine, Vol.22, pp.1-18
Publisher: BioMed Central Ltd.
Date published: 2024
DOI: 10.1186/s12967-024-05763-x
ISSN: 1479-5876
Copyright note: This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
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: 991068698702621
Output Type: Journal article

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