An effective scaffold-based vaccine (Vax) promoted massive and preferential monocyte expansion in the LNs. Addition of IL-2/anti-IL-2 (IL-2cx) significantly improved LN cDC1 expansion and activation while also enriching NK cells and CD8+ T cells at the Vax site. Vax+IL-2cx increased the number of peripheral, polyfunctional, antigen-specific CD8+ T cells (with a greater proportion of CD44+CD62L- effectors), and improved MC38 tumor control, dependent completely on cDC1s and partially on NK cells. In B16F10 tumors, Vax+IL-2cx reduced GzmB+ CD8+ T cells compared to Vax alone, yet enhanced NK and cDC1 infiltration, leading to modestly improved tumor control.
Contributed by Morgan Janes
ABSTRACT: One driver of the high failure rates of clinical trials for therapeutic cancer vaccines is likely the inability to sufficiently engage conventional dendritic cells (cDCs), the antigen-presenting cell (APC) subset that is specialized in priming antitumor T cells. Here, we demonstrate that, relative to vaccination with an injectable mesoporous silica rod (MPS) vaccine alone (Vax), combining MPS vaccines with CD122-biased IL-2/anti-IL-2 antibody complexes (IL-2cx) drives ~3-fold expansion of cDCs at the vaccination sites, vaccine-draining lymph nodes, and spleens of treated mice. Furthermore, relative to Vax alone, Vax+IL-2cx led to a ~3-fold increase in the numbers of CD8(+) T cells and ~15-fold increase in the numbers of NK cells at the vaccination site. Notably, with both the model protein antigen OVA as well as various peptide neoantigens, Vax+IL-2cx induced ~5 to 30-fold greater numbers of circulating antigen-specific CD8(+) T cells relative to Vax alone. We further demonstrate that Vax+IL-2cx leads to significantly improved efficacy in the MC38 colon carcinoma model relative to either monotherapy alone, driving complete regressions in 50% of mice in a cDC-dependent manner. Relative to vaccine alone, Vax+IL-2cx led to comparable numbers of CD8(+) T cells, but markedly greater numbers of NK cells and activated cDCs in the B16F10 melanoma tumor microenvironment post-therapy. Taken together, these findings suggest that the administration of factors that engage both the cDC-CD8(+) T cell and cDC-NK cell axes can boost the potency of therapeutic cancer vaccines.
