Lymph node lymphatic PD-L1 regulates tumor-infiltrating T cells in immune checkpoint-sensitive melanoma

Abstract

Lymph node (LN)-resident lymphatic endothelial cells (LECs) form the interphase between the lymphatic sinus lumen and the LN cortex. Beyond their role in leukocyte trafficking, LECs shape immune responses as they scavenge and (cross-) present exogenous antigens from the afferent lymph and constitutively express immune-regulatory proteins such as PD-L1. However, it remains unclear which immune cell types and activation states are sensitive to LN lymphatic PD-L1, and whether lymphatic PD-L1 expression is relevant for immune checkpoint blockade (ICB) sensitivity in cancer patients. To dissect the contribution of LN lymphatic PD-L1 to tumor immunity and ICB outcomes in melanoma, we utilized a conditional lymphatic PD-L1 knock-out mouse model in combination with syngeneic melanoma models varying in ICB sensitivity. While lymphatic PD-L1 deletion did not alter primary tumor growth, progression, or the overall immune landscape within tdLNs, it modulated the intratumoral immune composition in ICB-sensitive but not in ICB-resistant melanoma. Specifically, lymphatic PD-L1 deletion resulted in an increased frequency of proliferating PD-1+ CD8+ T cells and a reduction in PD-1+ Th1 T cells. Together, our findings reveal that lymphatic PD-L1 plays a context-dependent role in shaping anti-tumor T cell responses, particularly in ICB-sensitive disease.