The sentinel or tumor-draining lymph node (tdLN) serves as metastatic niche for many solid tumors and is altered via tumor-derived factors that support tumor progression and metastasis. TdLNs are often removed surgically, and therapeutic vaccines against tumor antigens are typically administered systemically or in non-tumor-associated sites. Although the tdLN is immune suppressed, it is also antigen-experienced through drainage of tumor-associated antigens (TAA), so we asked whether therapeutic vaccines targeting the tdLN would be more or less effective than those targeting the non-tdLN. Using LN-targeting nanoparticle (NP) conjugate vaccines consisting of TAA-NP and CpG-NP, we compared delivery to the tdLN vs. non-tdLN in two different cancer models, E.G7-OVA lymphoma (expressing the non-endogenous TAA ovalbumin) and B16-F10 melanoma. Surprisingly, despite the immune suppressed state of the tdLN, tdLN-targeting vaccination induced substantially stronger cytotoxic CD8+ T cell responses both locally and systemically than non-tdLN-targeting vaccination, leading to enhanced tumor regression and host survival. This improved tumor regression correlated with a shift in the tumor-infiltrating leukocyte repertoire towards a less suppressive and more immunogenic balance. NP-coupling of adjuvant and antigen was required for effective tdLN targeting, as NP-coupling dramatically increased the delivery of antigen and adjuvant to LN-resident antigen-presenting cells, thereby increasing therapeutic efficacy. This work highlights the tdLN as a target for cancer immunotherapy and shows how its antigen-experienced but immune suppressed state can be reprogrammed with a targeted vaccine yielding anti-tumor immunity.
- Received January 31, 2014.
- Accepted February 4, 2014.
- Copyright © 2014, American Association for Cancer Research.