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Patients with metastatic breast cancer were vaccinated with dendritic cell (DC) vaccines targeting HER2, and all seven survived >18 years. PBMC analysis revealed HER2-specific CD27⁺ memory CD4⁺ and CD8⁺ T cells, suggesting that CD27 signaling supports durable immune memory. We tested this by combining an anti-CD27 agonist antibody (Varlilumab) with a HER2 vaccine, which enhanced HER2-specific responses, particularly long-lived CD4⁺ memory T cells detectable up to 300 days post-vaccination. Transient CD27 agonism was observed in CD4+ T cells by scRNAseq and resulted improved tumor control (~40% regression) compared to vaccine alone (~6%), and synergy with PD-1 blockade led to complete tumor rejection in ~90% of mice. CD4⁺ T cells were essential for this effect, as shown by depletion and adoptive transfer experiments, while CD8⁺ T cells played a less critical role. These findings demonstrate that antigen-specific huCD27⁺ CD4⁺ T cells are key effectors of vaccine-induced immunity and support CD27 agonism as a promising strategy to enhance therapeutic cancer vaccination.

One Sentence Summary: CD27 signaling is essential for CD4⁺ T cell activation during vaccination and enable robust and long-lasting anti-tumor responses, which are independent of CD8⁺ T cells, but can also enhance their function.