Localized, sustained presentation of VEGF-C in mouse dermis alters the local immune microenvironment

Lymphangiogenesis is induced in areas of chronic inflammation, including in both autoimmunity (associated with immunoreactivity) and in many solid tumors (associated with metastases and immunosuppression). We asked whether and how local VEGF-C-driven lymphangiogenesis alone could affect adaptive immunity to a model antigen. To this end, we designed a hydrogel system for sustained local delivery of the lymphangiogenic protein VEGF-C. These proteins were engineered to express a peptide tag which are covalently crosslinkable onto the hydrogel matrix, and are thus better retained by the hydrogels. Following implantation into healthy mice, local delivery of VEGF-C increased lymphangiogenesis at the implant site as well as at the draining lymph nodes compared to empty hydrogel controls. This promoted increased local expression of CCL21, similar to observations in lymphangiogenic tumors, and associated with increased recruitment of CCR7 + cells, most notably CD4 T cells expressing markers of naive or memory phenotypes. To further examine the immunological relevance of these observations on antigen-specific T cell populations, hydrogels delivering both VEGF-C and the model antigen OVA were implanted into healthy mice which had previously received an adoptive transfer of OT-II T cells. These hydrogels also recruited CD4 T cells expressing markers of naive and memory phenotypes. Our studies suggest a role for lymphangiogenesis in the recruitment of immune cells during inflammation.