Systemic vaccination induces CD8 + T cells and remodels the tumor microenvironment

SUMMARYTherapeutic cancer vaccines are designed to increase tumor-specific T cell immunity. However, suppressive mechanisms within the tumor microenvironment (TME) may limit T cell function. Here we assessed how the route of vaccination alters intratumoral myeloid cells. Using a self-assembling nanoparticle vaccine that links tumor antigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we treated tumor-bearing mice subcutaneously (SNP-SC) or intravenously (SNP-IV). Both routes generated antigen-specific CD8 + T cells that infiltrated tumors. However, only SNP-IV mediated tumor regression, dependent on systemic type I interferon at the time of boost. Single cell RNA-sequencing revealed that intratumoral monocytes expressing an immunoregulatory gene signature ( Chil3 , Anxa2 , Wfdc17 ) were reduced after SNP-IV boost. In humans, the Chil3 + monocyte gene signature is enriched in CD16 monocytes and associated with worse outcomes. Our results show that the generation of tumor-specific CD8 + T cells combined with remodeling of the TME is a promising approach for tumor immunotherapy.Graphical AbstractIn BriefIntravenous administration of a cancer vaccine promotes tumor regression via antigen-specific CD8 + T cells and type I interferon-dependent modulation of the tumor microenvironment.