Lymphatic PD-L1 expression restricts tumor-specific CD8+ T cell responses

Lymph node (LN)-resident lymphatic endothelial cells (LECs) mediate peripheral tolerance by self-antigen presentation on MHC-I and constitutive expression of T cell inhibitory molecules, including PD-L1. Tumor-associated LECs also upregulate PD-L1 but the specific role of lymphatic PD-L1 in tumor immunity is not well understood. We generated a mouse model lacking lymphatic PD-L1 expression and challenged these mice with two orthotopic tumor models, B16F10 melanoma and MC38 colorectal carcinoma. Lymphatic PD-L1 deficiency resulted in a consistent expansion of tumor-specific CD8+ T cells in tumor-draining LNs in both tumor models, reduced primary tumor growth in the MC38 model, and increased the efficacy of adoptive T cell therapy in the B16F10 model. Strikingly, lymphatic PD-L1 primarily acted via apoptosis induction in tumor-specific CD8+ central memory T cells. Our findings demonstrate that LECs restrain tumor-specific immunity via PD-L1 and may explain why some cancer patients without PD-L1 expression in the tumor microenvironment still respond to PD-L1 / PD-1 targeting immunotherapy.