The PD-1/PD-L1-Checkpoint Restrains T cell Immunity in Tumor-Draining Lymph Nodes

PD-1/PD-L1-checkpoint blockade therapy is generally thought to relieve tumor cell-mediated suppression in the tumor microenvironment but PD-L1 is also expressed on non-tumor macrophages and conventional dendritic cells (cDCs). Here we show in mouse tumor models that tumor-draining lymph nodes (TDLNs) are enriched for tumor-specific PD-1+ T cells which closely associate with PD-L1+ cDCs. TDLN-targeted PD-L1-blockade induces enhanced anti-tumor T cell immunity by seeding the tumor site with progenitor-exhausted T cells, resulting in improved tumor control. Moreover, we show that abundant PD-1/PD-L1-interactions in TDLNs of nonmetastatic melanoma patients, but not those in corresponding tumors, associate with early distant disease recurrence. These findings point at a critical role for PD-L1 expression in TDLNs in governing systemic anti-tumor immunity, identifying high-risk patient groups amendable to adjuvant PD-1/PD-L1-blockade therapy. [Display omitted] •Tumor-draining lymph nodes (TDLNs) are enriched for tumor-specific PD-1+ T cells•Blocking PD-L1 in TDLNs generates progenitor-exhausted T cells that seed the tumor•PD-L1 blockade on cDCs, not macrophages in TDLNs induces effective tumor immunity•PD-1/PD-L1 interactions in TDLN but not tumor correlate with prognosis in melanoma Dammeijer et al. show that PD-1/PD-L1 interactions occur frequently in tumor-draining lymph nodes (TDLNs) and that specific targeting of PD-L1 in the TDLN induces an effective anti-tumor immune response in multiple mouse models. In addition, PD-1/PD-L1 interactions in TDLNs, but not in tumor, correlate with prognosis in melanoma patients.