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

Dammeijer, Floris; van Gulijk, Mandy; Mulder, Evalyn E; Lukkes, Melanie; Klaase, Larissa; van den Bosch, Thierry; van Nimwegen, Menno; Lau, Sai Ping; Latupeirissa, Kitty; Schetters, Sjoerd; van Kooyk, Yvette; Boon, Louis; Moyaart, Antien; Mueller, Yvonne M; Katsikis, Peter D; Eggermont, Alexander M; Vroman, Heleen; Stadhouders, Ralph; Hendriks, Rudi; Thüsen, Jan von der; Grünhagen, Dirk J; Verhoef, Cornelis; van Hall, Thorbald; Aerts, Joachim G

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.