PD-L1 couples with LTβR signaling to accelerate tumor growth and metastasis
Jewell, Christopher M.
Bromberg, Jonathan Scott
MetadataShow full item record
AbstractTregs accumulate in the tumor microenvironment, constrain anti-tumor immunity, and are critical targets for anti-tumor strategies. We previously showed that Tregs use surface lymphotoxin (LTαβ) and PD-1 to signal LTβR and PD-L1 on lymphatic endothelial cells (LECs), thereby promoting Treg lymphatic transendothelial migration (TEM)1,2 . Most tumor cells express LTβR and PD-L1, yet tumor interactions with LTαβ and PD-1 on Tregs are poorly studied. Here we investigate whether PD-L1 couples with LTβR signaling on tumors or LECs to regulate cell migration and tumor metastasis. Results show PD-L1 bound to LTβR in resting B16F10 melanoma cell and PD-L1 deficiency enhanced LTβR expression and apoptosis. Blocking LTβR-nonclassical NFB-NIK signaling increased melanoma PD-L1 expression but decreased tumor TEM. RNASeq analysis of B16F10 revealed that genes regulated by LTβR nonclassical NFB signaling were increased by PD-L1 depletion. LTβR activation promoted B16F10 TEM, and PD-L1 deficiency abolished the enhancement, indicating PDL1 is required for LTbR signaling mediated tumor TEM. Tregs but not effector T cells can directly activate B16F10 LTbR-nonclassical NFB signaling, suggesting a critical role of Treg LT-tumor LTbR signaling for tumor metastasis. In vivo, PD-L1 blockade combined with LTβR classical or nonclassical NFB blocking peptides inhibited tumor growth and metastases, and enhanced host survival. Overall, PD-L1 couples with LTβR-nonclassical NFB signaling to regulate tumor growth and migration. Blocking both arms of tumor LTβR-NFκB-signaling enhanced immune checkpoint blockade efficacy and tumor bearing mouse survival. These observations provide a rational strategy to modulate Treg activities to prevent tumor spread.
Rights/TermsAttribution-NonCommercial-NoDerivatives 4.0 International
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/20573
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International