Intraperitoneal administration of cationic liposomes containing a TLR3 agonist recruits type I conventional dendritic cells and primes a local CD8+ T cell response

Background: Therapeutic vaccines capable of eliciting CD8 T cell responses are a promising approach in cancer, but the magnitude of immune responses to peptide-based vaccine technologies has so far been modest in humans. The cationic liposome adjuvant CAF®09b has recently shown promising results in clinical trials, where it is administered intraperitoneally (i.p.), as preclinical studies demonstrated superior CD8 T cell responses when using this route compared to subcutaneous delivery. Methods: Exploring the mechanism of CAF09b in mice we investigated biodistribution of the adjuvant and associated antigen in murine studies. We further examined local innate cell recruitment and CD8 T cell responses in the peritoneal cavity. Findings: We observed that i.p. injected CAF09b associated with visceral fatty tissues and created a vaccine depot in the peritoneal cavity. This led to recruitment of BATF3-dependent conventional type I dendritic cells (cDC1) displaying a migratory cDC1 phenotype (CD11c+XCR1+CD103+). Gene ontology analysis further revealed similarities with visceral adipose tissue DCs. CAF09b injection i.p. led to early priming of CD8 T cells localized to the peritoneal cavity and this response was resistant to FTY720 treatment. Interpretation: This study demonstrates that adjuvants can facilitate recruitment of cDC1s to the peritoneal cavity, a feature that may contribute to the effectiveness of i.p. administration on elicitation of CD8 T cell responses. Furthermore, we demonstrate that CAF09b-induced CD8 T cell responses require BATF3-dependent cDC1 cells. Understanding cDC1 and CD8 T cell dynamics via different immunization routes may aid in the design of more effective vaccine strategies. Funding: This work was primarily supported by the Danish Research Council (FTP fund no. 9041-00131b).