Abstract
Lymph node (LN)–resident lymphatic endothelial cells (LEC) mediate peripheral tolerance by self-antigen presentation on MHC-I and constitutive expression of T-cell inhibitory molecules, including PD-L1 (CD274). Tumor-associated LECs also upregulate PD-L1, but the specific role of lymphatic PD-L1 in tumor immunity is not well understood. In this study, 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 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 efficacy of adoptive T-cell therapy in the B16F10 model. Strikingly, lymphatic PD-L1 acted primarily by inducing apoptosis in tumor-specific CD8+ central memory T cells. Overall, these findings demonstrate that LECs restrain tumor-specific immunity via PD-L1, which may explain why some patients with cancer without PD-L1 expression in the tumor microenvironment still respond to PD-L1/PD-1–targeted immunotherapy. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000500391Publication status
publishedExternal links
Journal / series
Cancer ResearchVolume
Pages / Article No.
Publisher
American Association for Cancer ResearchOrganisational unit
03683 - Detmar, Michael (emeritus) / Detmar, Michael (emeritus)
Funding
166490 - The role of lymphatic vessels in cancer progression (SNF)
185392 - Role of lymphatic vessels in cancer progression (SNF)
More
Show all metadata