mRNA-based immunotherapy improves the efficacy of adoptively transferred TCR transgenic T cells in a murine solid tumour model

Abstract Adoptive T cell therapy (ACT) has shown remarkable clinical success in treating haematological malignancies; however, its efficacy against solid tumours remains limited. This is largely due to poor persistence and functionality of transferred T cells, restricted tumour infiltration, and the presence of an immunosuppressive tumour microenvironment. Here, using the MC38-OVA murine tumour model, we tested whether combining Transgenic T cell receptor (TCR tg ) T cell therapy with an adjunctive mRNA-based immunotherapy could address these challenges and drive effective and long-lasting anti-tumour response. Tumour-bearing mice were treated with different numbers of in vivo-activated, ovalbumin (OVA)-specific TCR tg CD8 + T cells harvested from OT-I mice, either alone or in combination with lipid nanoparticle (LNP)-encapsulated mRNA encoding OVA. Tumour progression was monitored, and analyses were performed to assess survival, T cell expansion, phenotype, infiltration, and effector function. The combination therapy of a low dose of TCR tg T cells and mRNA immunotherapy led to robust and durable anti-tumour responses, significantly improving survival compared to monotherapies. Notably, transferred TCR tg T cells expanded only following mRNA immunotherapy, and circulating TCR tg T cells exhibited a memory precursor and effector memory phenotype. These cells infiltrated tumours effectively and displayed more potent cytotoxic activity, resulting in regression of large tumours—even without prior lymphodepletion. Overall, our findings demonstrate that mRNA immunotherapy can substantially enhance the efficacy of TCR tg T cell therapy in a solid tumour model. This combinatorial approach holds promise for overcoming key limitations of ACT by boosting T cell expansion, persistence, infiltration, and functional capacity within the tumour microenvironment.