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Dual-antigen Doggybone DNA vaccine induces potent anti-tumour immunity against immunosuppressive oral cancer

ABSTRACT: Immunotherapy has demonstrated durable responses in a subset of patients with head and neck cancer, offering potential survival benefits to those with poor prognoses and resistance to first-line treatments. Despite this, only a modest 15-20% are shown to respond. Cancer vaccines have recently demonstrated efficacy in some solid tumours including melanoma, as well as immune-cold pancreatic and liver cancer, inducing a cytotoxic T cell response and eradicating cancer cells. Our previous research identified cancer testis antigens MAGED4B and FJX1 as highly immunogenic and overexpressed in the majority of HPV-independent head-and-neck squamous cell carcinoma (HPVnegHNSCC) patients. In this study, we developed a novel DNA vaccine utilising the non-plasmid doggyboneTM (dbDNATM) platform to deliver these antigens for targeting head and neck cancer. A series of doggyboneTM vaccine prototypes targeting MAGED4B and FJX1 were generated both to optimise the backbone and to present antigens in an immunogenic form. Vaccine immunogenicity and cytotoxicity were accessed using interferon-gamma. Enzyme-Linked Immunospot (ELISpot) assay. Vaccine efficacy was evaluated in the MOC-2 oral cancer model through tumour monitoring, assessing the infiltration of CD4+, CD8+ and regulatory T cells by immunohistochemistry as well as RNAseq analysis. The optimised dual antigen dbDNA DNA vaccine significantly reduced tumour size. Furthermore, combining the vaccine with anti-PD1 therapy significantly delayed tumour growth and metastasis, thereby enhancing survival in tumour-bearing mice. Vaccination resulted in significant recruitment of CD4+ and CD8+ T cells but not regulatory T cells. IHC analysis also confirmed the ability of dbDNA™ vaccine TGL-100 OPT in shifting M2 to M1 polarisation, highlighting their therapeutic promise. Transcriptomic analysis of immune cells in the tumour indicates that vaccination promotes long term anti-tumour responses by upregulating memory T cell genes T cell factor-7 (Tcf7) and lymphoid enhancer binding factor 1 (Lef1) while suppressing PDL-1 and inhibiting anti-inflammatory cytokines such as IL-10 and IL-27. These findings suggest that our cancer vaccine effectively recruits cytotoxic T cells to immune cold tumours, minimising the host’s immune inhibitory mechanisms within the tumour and resulting in long-term protection against head and neck cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE310571 | GEO | 2025/12/01

REPOSITORIES: GEO

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Project description:This study aimed to analyse the effect of immunotherapeutic treatment with ChAdOx/MVA MAGE vaccine and anti-PD-1 on the transcriptional mRNA profiles of murine 15V4T3 tumours. 15V4T3 tumour-bearing mice were treated with either a PBS control, anti-PD-1 inhibitor (3-doses of 100 µg 3-days apart), ChAdOx/MVA P1A vaccine (10^7 IU / 10^6 PFU doses 1-week apart), or with a combination of vaccine + anti-PD-1. Following treatment, RNA was isolated from tumour tissue samples and then tumour transcriptomic gene expression profiles were analysed by RNA-sequencing. Sequenced reads were mapped to the mouse genome GRCm38. A counts matrix reporting the numbers of reads mapping to each gene was then generated, and abundance measurements performed using TMM-normalized (EdgeR) counts data to quantify gene expression levels. 14937 expressed transcripts were identified as expressed above a minimum threshold. Results from the transcriptomic analysis indicated that ChAdOx/MVA P1A vaccination had a profound effect on the gene expression profiles of 15V4T3 tumours. Approximately 1250 differentially expressed genes were identified in tumours from vaccinated compared to unvaccinated mice using a threshold for differential expression of fold change > 2 and Padj < 0.05. Furthermore, gene expression signatures corresponding to a CD8+ T-cell driven inflammatory response and an IFNg response were found to be highly enriched in tumours from vaccinated mice. Such gene expression signatures have been found in other studies to be predictive of response to immunotherapy and anti-PD-1 immune checkpoint blockade. GSVA further confirmed the enrichment of gene sets corresponding to immune activation, a pro-inflammatory response and T-cell activity in the mRNA expression data from tumours of vaccinated mice compared to unvaccinated. Taken together these findings show that a ChAdOx/MVA vaccine targeting a MAGE type antigen can generate and drive tumour gene expression patterns associated with a T-cell inflammatory response and positive response to cancer immunotherapy.

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Dual-antigen Doggybone DNA vaccine induces potent anti-tumour immunity against immunosuppressive oral cancer

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