PD-L1 couples with LTβR signaling to accelerate regulatory T cell lymphatic migration and tumor metastasis

Abstract Introduction: Tregs in the tumor environment inhibit anti-tumor immunity and are critical targets for strategies. We previously showed that use surface lymphotoxin (LTαβ) PD-1 to signal LTβR PD-L1 on lymphatic endothelial cells, thereby promoting Treg migration. Most cells express PD-L1, yet interactions with LTαβ poorly studied. hypothesized couples signaling tumors regulate migration metastasis. Methods: Wild type CRISPR/Cas9 or knockout B16F10 melanoma were used cell Specific classical nonclassical NFκB blocking peptides used. Results: bound resting B16F10, LTβR-nonclassical increased expression. RNASeq analysis of revealed gene expression regulated by was depletion, while genes driven remained unaltered depletion. Melanoma cocultured had enhanced migration, combined blockade pathways synergistically blocked In vivo, inhibited growth metastases, host survival. Conclusions: Blocking both arms LTβR-NFκB-signaling immune checkpoint efficacy mouse These observations provide a rational strategy modulate activities prevent spread. supported NIH R37 AI062765 Emerald grant 2022