Medical School of Guizhou University, Guiyang, Guizhou, 550000, China.
Cancer Research Institute, First People's Hospital of Foshan, Foshan, Guangdong, 528000, China.
J Transl Med. 2024 Oct 28;22(1):973. doi: 10.1186/s12967-024-05763-x.
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.
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.
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 CD4CD8 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 CD4CD25 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 Arg1 macrophages, and activation of pro-inflammatory pathways in MHCII and tissue-resident macrophages.
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.
癌症免疫疗法，特别是免疫检查点抑制剂（ICB），如抗 PD-1 抗体，已经彻底改变了癌症治疗，尽管患者之间的反应率有所不同。先前的研究表明，来自澳大利亚树蛙的宿主防御肽 caerin 1.1 和 1.9 通过在肿瘤内激活肿瘤相关巨噬细胞，增强了抗 PD-1 和治疗性疫苗在 TC-1 小鼠模型中的有效性。
我们采用小鼠 B16 黑色素瘤模型研究了 caerin 1.1 和 1.9 与抗 CD47 和治疗性疫苗（三联疗法，TT）联合使用的治疗潜力。评估了注射 caerin 的原发性肿瘤和远处转移瘤的肿瘤生长，并进行了生存分析。对来自远处肿瘤的 CD45 细胞进行单细胞 RNA 测序（scRNAseq），以阐明 TT 诱导的肿瘤微环境变化。
与未治疗组和对照组相比，TT 治疗显著降低了治疗侧的肿瘤体积，在第 21 天观察到了显著的效果。生存分析表明，接受 TT 治疗的小鼠在治疗侧和远处侧的生存时间都延长了。scRNAseq 显示，TT 组中传统 1 型树突状细胞（cDC1）和 CD4CD8 T 细胞显著扩增。TT 组中的肿瘤相关巨噬细胞向更具免疫反应性的 M1 表型转变，观察到 cDC1 与 CD8 和 CD4CD25 T 细胞之间的增强通讯。此外，TT 下调了 M2 样巨噬细胞标记基因，特别是在 MHCIIhi 和组织驻留巨噬细胞中，抑制了所有巨噬细胞类型的 Cd68 和 Arg1 表达。差异基因表达分析突出了通路改变，包括 Arg1 巨噬细胞中氧化磷酸化和 MYC 靶标 V1 的上调，以及 MHCII 和组织驻留巨噬细胞中促炎途径的激活。
我们的研究结果表明，caerin 1.1 和 1.9 与免疫疗法联合使用，有效地调节了原发性和继发性肿瘤中的肿瘤微环境，导致肿瘤生长减少和全身免疫增强。对这些机制的进一步研究可能为晚期黑色素瘤治疗中改进的联合治疗铺平道路。
