Dendritic cell PD-L2 restrains intratumoral CD8+ T cell immunity

Abstract

Blockade of inhibitory PD-1 signaling on T cells is a cornerstone of cancer immunotherapy, with current strategies targeting PD-1 or its ligand PD-L1. However, PD-1 engages an alternative ligand, PD-L2, whose role in tumor immunity remains poorly defined. Here, we show that PD-L2 is upregulated on intratumoral CCR7+ conventional dendritic cells (cDCs) in both mouse and human melanoma. Using genetic mouse models enabling selective ablation of PD-L1 or PD-L2 in cDCs, we identify a division of labor between these ligands: PD-L1 controls the size of the progenitor CD8 T cell pool in tumor-draining lymph nodes by modulating stem-like CD8 T cells, whereas PD-L2 limits progenitor exhausted CD8 T cell differentiation within the tumor microenvironment. Loss of PD-L2 in cDCs enhances cytotoxic CD8 T cell responses and suppresses tumor growth, particularly in tumors enriched for CCR7+ cDC1s. Consistent with this, increased CCR7+ cDC abundance is associated with poor prognosis in human cancers. Spatial transcriptomic analyses reveal co-localization of CCR7+ cDC1s and Tpex within CCL19hi niches, where cancer-associated fibroblasts serve as the predominant source of CCL19. Finally, intratumoral GM-CSF drives PD-L2 expression on CCR7+ cDCs, with Tpex and NK cells as major sources. Together, these findings establish cDC-associated PD-L1 and PD-L2 as spatially and functionally distinct checkpoints governing CD8 T cell differentiation. Our results suggest that the abundance of CCR7+ cDC1s may guide the choice between anti-PD-1 and anti-PD-L1 therapies and support the development of PD-L2-directed blockade.