Intradermally injected nanoparticle (NP)- to microparticle (MP)-sized fluorescent tracers accumulated in draining lymph nodes (dLNs) with differential kinetics, localization, and cell type association. Conjugated to OVA peptide, NPs induced more stem-like CD8+ T cells relative to MPs, which elicited more cytotoxic effectors. B16F10 intratumoral (versus naive intradermal) injection increased MP, but not NP, dLN accumulation and cellular OVA presentation. More than tumors or spleens, tumor dLNs supported the viability, proliferation, and stemness of transferred T cells, and tdLN-targeted anti-PD-1 treatment was more effective than systemic delivery.
Contributed by Alex Najibi
ABSTRACT: Revealing the mechanisms that underlie the expansion of antitumor CD8(+) T cells that are associated with improved clinical outcomes is critical to improving immunotherapeutic management of melanoma. How the lymphatic system, which orchestrates the complex sensing of antigen by lymphocytes to mount an adaptive immune response, facilitates this response in the context of malignancy is incompletely understood. To delineate the effects of lymphatic transport and tumor-induced lymphatic and lymph node (LN) remodeling on the elicitation of CD8(+) T cell immunity within LNs, we designed a suite of nanoscale biomaterial tools enabling the quantification of antigen access and presentation within the LN and resulting influence on T cell functions. The expansion of antigen-specific stem-like and cytotoxic CD8(+) T cell pools was revealed to be sensitive to the mechanism of lymphatic transport to LNs, demonstrating the potential for nanoengineering strategies targeting LNs to optimize cancer immunotherapy in eliciting antitumor CD8(+) T cell immunity.