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.
Author Info: (1) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138. Wyss Institute for Biologically Inspired Engineering at Harvard University,
Author Info: (1) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215. (2) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215. (3) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215. (4) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215. (5) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215. (6) Department of Cancer Immunology, Genentech, Inc., South San Francisco, CA 94080. (7) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215. (8) Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215. (9) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215. (10) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215. (11) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215. Harvard Program in Biophysics, Harvard University, Cambridge, MA 02138. (12) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215. (13) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva CH-1211, Switzerland. Ludwig Institute for Cancer Research, Lausanne CH-1005, Switzerland. Agora Cancer Center, Lausanne CH-1005, Switzerland. (14) Department of Cancer Immunology, Genentech, Inc., South San Francisco, CA 94080. Department of Neurological Surgery, University of California, San Francisco, CA (15) Department of Cancer Immunology, Genentech, Inc., South San Francisco, CA 94080. (16) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02215.
