Abstract C069: Leveraging cDC1 populations for enhanced mRNA cancer vaccination

Abstract mRNA vaccines have revolutionized the efficiency of vaccine development against infectious diseases, enabled through the development of enhanced mRNA delivery systems such as lipid nanoparticles (LNPs) coupled with molecular tools to circumvent mRNA innate immunogenicity, including the incorporation of nucleoside base modifications such as N1-methylpseudouridine. Despite these advances, vaccine formulations for infectious diseases may not be optimal for use in cancer due to differential determinants of immunity. There is a clear lack of consensus on the optimal mRNA cancer vaccine strategy, with mRNA vaccines trialed clinically in cancer exhibiting different designs in terms of the mRNA base modifications and lipid-based delivery platforms utilized, warranting further study. An ideal cancer vaccine should elicit robust anti-tumor cytotoxic CD8+ T and CD4+ Th1 cell responses, orchestrated by specialized antigen-presenting cell populations such as conventional type-1 dendritic cells (cDC1). cDC1 frequency, activity and functionality are often impaired in the tumor microenvironment (TME) and reduced cDC1 intratumoral infiltration correlates with poor prognosis and disease progression. Therefore, determining how mRNA vaccination strategies can be designed to enhance cDC1 activation and expansion, for more effective induction of anti-tumor immunity is essential. Our study identifies a key role for cDC1s in mRNA vaccine efficacy, and characterizes the contribution of mRNA modification, lipid-based delivery platform and immunization route to vaccine efficacy. Additionally, we demonstrate an adjuvant strategy utilizing FLT3L encoding mRNA to promote the expansion and activity of intratumoral cDC1s. This adjuvant mRNA strategy exhibits therapeutic efficacy alone and in synergy with tumor-antigen directed mRNA vaccination. Ultimately, we aim to harness the non-redundant antitumor role of cDC1s to develop an optimal mRNA vaccination strategy for use in the prevention and treatment of cancer. Citation Format: Ross Ward, Aparna Anantharayanan, Guillaume Mestrallet, Xinying Ge, Ashley Reid-Cahn, Uddipan Kar, Nicolas Vabret, Sreekumar Balan, Nina Bhardwaj. Leveraging cDC1 populations for enhanced mRNA cancer vaccination [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C069.