Programmed cell death ligand 1 (PD-L1) inhibition in tumor naïve mice is bone-sparing throughout the lifespan

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ID: 320253
2026
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Ranked #20 of 143 articles by views in journal of bone and mineral research : the official journal of the american society for bone and mineral research

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Abstract
Abstract Immune checkpoint inhibitors (ICIs) which target immune checkpoint proteins like programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have revolutionized cancer therapy. Skeletal toxicities are emerging immune-related adverse events for patients treated with ICIs, and PD-1 blockade in pre-clinical mouse models significantly reduces bone mass. However, the effect of PD-L1 inhibition on the bone throughout development is not well understood. We investigated the role of PD-L1 loss on bone microarchitecture with genetic PD-L1 knockout in myeloid cells using LysM-Cre;PD-L1Flox/Flox mice and pharmacologic inhibition with a PD-L1 neutralizing antibody in adult and aged mice. We report that neither PD-L1 deletion in myeloid cells nor inhibition with α-PD-L1 significantly impacts femoral trabecular bone microarchitecture; however, α-PD-L1 treatment increases vertebral trabecular bone volume. Additionally, PD-L1 blockade influences T cell expansion by decreasing naïve T cells and increasing effector memory T cells in the bone marrow, consistent with previous studies on the effects of PD-1 inhibition. The trabecular bone-sparing effect of PD-L1 inhibition is strikingly different from the bone loss observed with PD-1 blockade. Clinical studies are necessary and justified to determine if PD-L1 may be a less bone destructive alternative for cancer patients treated with ICIs who are at high risk of fracture.
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Authors Madeline B Searcy, Gwenyth J. Joseph, Jeremy Kane, Laasya Challa, Hidenori Tanaka, Sasidhar Uppuganti, Jailyn A. Smith, Eben L. Rosenthal, David G. Harrison, Jeffry S. Nyman, Megan Weivoda, Rachelle W. Johnson
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Journal journal of bone and mineral research : the official journal of the american society for bone and mineral research
Year 2026
DOI
10.1093/jbmr/zjag104
URL
https://doi.org/10.1093/jbmr/zjag104
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