Glycan targeting can recruit anti-tumor immunologic functions by lymphatic endothelium

During carcinoma progression, CD8+ T cells mediate tumor-cytolytic functions following tumor-antigen sensitization, typically by antigen cross-presenting dendritic cells. Lymphatic endothelial cells (LECs) are not typically endowed with such immune-effector capacity, and often promote tolerance. Inspired by insights from dendritic-cell glycan targeting, we examined how antigen-pulsed lymph node LECs genetically deficient in Ndst1, expressing under-sulfated heparan sulfate, might affect antigen-sensitized CD8+ T cell responses. Mutation significantly augmented responses to Ova-peptide pulsed LECs, including marked Nur77 activation along with more modest IFN-γ induction in co-cultured Ova-responsive CD8+ T cells, and increased antigen presentation relative to wildtype LECs (without marked differences in MHC-I, CD86 or PD-L1 immune checkpoint ligands). Tumor draining lymph nodes of lymphatic targeted tumor-bearing Ndst1f/f Prox1Cre+ mutant mice showed reduced metastatic loads accompanied by augmented CD8+ T cell densities compared to Ndst1f/f Prox1Cre- controls. These findings provide mechanistic insight on harnessing glycan-targeted lymphatic endothelium to boost effector T cell immunity.