CpG 1018 augments mRNA vaccine-induced anti-tumor immunity by potentiating CD8+ T cell responses

Personalized neoantigen mRNA vaccines showed good efficacy in treating metastatic melanoma, pancreatic cancer, and breast cancer in early phase clinical trials. Strategies are needed to further enhance neoantigen mRNA vaccine-induced anti-tumor immunity. This study explored conventional adjuvant co-administration to enhance mRNA vaccine-induced anti-tumor immunity. We found a clinically used CpG 1018 adjuvant was highly effective to enhance ovalbumin (OVA) and neoantigen mRNA-induced T cell responses and anti-tumor immunity in B16F10-OVA melanoma models. Mechanistic studies found CpG 1018 mainly enhanced dendritic cell maturation and local cytokine/chemokine release but not mRNA translation. mRNA vaccine in the presence of CpG 1018 induced significantly higher levels of Granzyme B, IFNγ, and TNFα-secreting CD8+ T cells as compared to mRNA vaccine alone. We further found that potent anti-tumor immunity was associated with increased tumor-infiltration of CD8+ T cells and positively correlated with tumor-infiltrating CD8+ to CD4+ T cell ratios. Cell depletion studies found CD8+ T cells rather than CD4+ T cells or NK cells played crucial roles in CpG 1018-augmented mRNA vaccine efficacy. CpG 1018-adjuvanted mRNA vaccine induced transient body weight loss (<6%) with an overall good safety. Our data warrant further investigation of CpG 1018-adjuvanted neoantigen mRNA vaccine for potentially better tumor therapy.