Dataset Information

Topical application of temperature sensitive gel containing caerin 1.1 and 1.9 peptides on TC-1 tumour bearing mice modulates heterogeneity of macrophage and dendritic cell in the tumour microenvironment

ABSTRACT: In this study, we demonstrate that, the topical application of a temperature-sensitive gel containing caerin 1.1 and 1.9 peptides significantly reduces the tumour weight of HPV 16 E6/E7 transformed TC-1 tumour bearing mice via improving the tumour microenvironment (TME) when compared with untreated tumour or a control peptide-containing gel. We use single cell transcriptomics and TMT10 plex-labelling proteomics to quantify changes in cellular activity across different cell types within the TME. We show that caerin 1.1/1.9 gel increased immune activating macrophages, modulated the heterogeneity of NK and dendritic cells to be more pro-inflammatory, and increased numbers of activated CD8+ T cells. Proteomic profiling demonstrated higher innate immune responses, especially the positive regulations of interferon-alpha/beta secretion and response to cytokine stimulus in the caerin gel groups. Further, computational integration of the proteome with the single cell transcriptome consistently suggested more activated T cells and NK cells with the treatment of caerin peptide gel.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Tianfang Wang

LAB HEAD: Tianfang Wang

PROVIDER: PXD025779 | Pride | 2022-02-17

REPOSITORIES: Pride

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Topical Application of Temperature-Sensitive Gel Containing Caerin 1.1 and 1.9 Peptides on TC-1 Tumour-Bearing Mice Induced High-Level Immune Response in the Tumour Microenvironment.

Ni Guoying G Liu Xiaosong X Li Hejie H Fogarty Conor E CE Chen Shu S Zhang Pingping P Liu Ying Y Wu Xiaolian X Wei Ming Q MQ Chen Guoqiang G Zhang Ping P Wang Tianfang T

Frontiers in oncology 20211111

The development of topical cream drugs that increase the immune activation of tumour-infiltrating lymphocytes against tumour and chronic viral infection-associated lesions is of great immunotherapeutic significance. This study demonstrates that the topical application of a temperature-sensitive gel containing caerin 1.1 and 1.9 peptides reduces nearly 50% of the tumour weight of HPV16 E6/E7-transformed TC-1 tumour-bearing mice <i>via</i> improving the tumour microenvironment. Confocal microscopy ...[more]

PMID: 34858827

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Project description:Malignant germ-cell-tumours (GCTs) are characterised by microRNA (miRNA/miR-) dysregulation, with universal over-expression of miR-371~373 and miR-302/367 clusters regardless of patient age, tumour site, or subtype (seminoma/yolk-sac-tumour/embryonal carcinoma). These miRNAs are released into the bloodstream, presumed within extracellular-vesicles (EVs) and represent promising biomarkers. Here, we comprehensively examined the role of EVs, and their miRNA cargo, on (fibroblast/endothelial/macrophage) cells representative of the testicular GCT (TGCT) tumour microenvironment (TME). Small RNA next-generation-sequencing was performed on 34 samples, comprising representative malignant GCT cell lines/EVs and controls (testis fibroblast [Hs1.Tes] cell-line/EVs and testis/ovary samples). TME cells received TGCT co-culture, TGCT-derived EVs, and a miRNA overexpression system (miR-371a-OE) to assess functional relevance. TGCT cells secreted EVs into culture media. MiR-371~373 and miR-302/367 cluster miRNAs were overexpressed in all TGCT cells/subtypes compared with control cells and were highly abundant in TGCT-derived EVs, with miR-371a-3p/miR-371a-5p the most abundant. TGCT co-culture resulted in increased levels of miRNAs from the miR-371~373 and miR-302/367 clusters in TME (fibroblast) cells. Next, fluorescent labelling demonstrated TGCT-derived EVs were internalised by all TME (fibroblast/endothelial/macrophage) cells. TME (fibroblast/endothelial) cell treatment with EVs derived from different TGCT subtypes resulted in increased miR-371~373 and miR-302/367 miRNA levels, and other generic (eg, miR-205-5p/miR-148-3p) and subtype-specific (seminoma, eg, miR-203a-3p; yolk-sac-tumour, eg, miR-375-3p) miRNAs. MiR-371a-OE in TME cells resulted in increased collagen contraction (fibroblasts) and angiogenesis (endothelial cells), via direct mRNA downregulation and alteration of relevant pathways. TGCT cells communicate with nontumour stromal TME cells through release of EVs enriched in oncogenic miRNAs, potentially contributing to tumour progression.

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