Dendritic cell PD-L2 restrains intratumoral CD8+ T cell immunity
- 1Memorial Sloan Kettering Cancer Center
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.
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BibTeX
@misc{nah2026dendritic,
title = {{Dendritic cell PD-L2 restrains intratumoral CD8+ T cell immunity}},
author = {J. Nah and A. Sun and A. Yadav and A. Scheinfeld and T. Azad and S. Rose and B. Becher and J. W. Smithy and M. A. Postow and C. E. Ariyan and Y. Pritykin and C. Brown},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.10.750646},
url = {https://www.biorxiv.org/content/10.64898/2026.09.10.750646v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Dendritic cell PD-L2 restrains intratumoral CD8+ T cell immunity
AU - J. Nah
AU - A. Sun
AU - A. Yadav
AU - A. Scheinfeld
AU - T. Azad
AU - S. Rose
AU - B. Becher
AU - J. W. Smithy
AU - M. A. Postow
AU - C. E. Ariyan
AU - Y. Pritykin
AU - C. Brown
PY - 2026
DA - 2026/09/10
PB - bioRxiv
DO - 10.64898/2026.09.10.750646
UR - https://www.biorxiv.org/content/10.64898/2026.09.10.750646v1
AB - 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.
ER -