Recurrent RNA-lipoplex vaccination is required to sustain functional tumor-infiltrating neoantigen-specific CD8 T cells and therapeutic efficacy
Gibson, J. T.; Hornburg, M.; Lehar, S.; Javinal, V.; Liao, L.; McCarron, M. J.; Jones, T. N.; Oei, Y.; Dunlap, D.; Marroquin, K. A.; Lo, A. A.; Bergman, J. H.; Tong, A.-J.; Nissenbaum, A.; Freund, E. C.; Capietto, A.-H.; de la Cruz, C. C.; Sahin, U.; Mellman, I.; Schartner, J. M.; Delamarre, L.
Show abstract
Cancer vaccines induce durable, polyepitopic T cell responses, and show promising clinical benefit in adjuvant settings, yet they are largely ineffective in advanced disease. Using a clinically relevant RNA-lipoplex vaccine, we investigated the efficacy constraints in a preclinical model. Vaccination remodeled the tumor microenvironment (TME), increasing T cell infiltration and promoting a proinflammatory myeloid compartment. This was associated with complete regression of smaller, immature tumors, but only delayed growth of larger, established tumors. While vaccine-induced T cells were long-lived and functional in peripheral tissues, intratumoral T cells declined rapidly in abundance, diversity, and function, reverting to a prevaccine-like state. scRNA-seq suggested that this was driven by a pro-apoptotic program, with surviving T cells showing signatures of cellular stress and impaired activation. Importantly, recurrent vaccination replenished functional T cells in the TME and enhanced efficacy. These findings highlight the importance of optimizing vaccine schedules and tailoring therapeutic strategies to tumor stage.
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