Joseph Gwenyth J, Vecchi Iii Lawrence A, Uppuganti Sasidhar, Kane Jeremy F, Durdan Margaret, Hill Paige, McAdoo Ashtyn G, Tanaka Hidenori, Kell David, Searcy Madeline B, Chen Wei, Rosenthal Eben L, Harrison David G, Nyman Jeffry S, Weivoda Megan M, Johnson Rachelle W
Graduate Program in Cancer Biology, Vanderbilt University, Nashville, TN, 37232.
Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, 37232.
J Bone Miner Res. 2025 Jul 28;40(8):950-964. doi: 10.1093/jbmr/zjaf055.
Immune checkpoint inhibitors (ICIs) block immunoregulatory receptor-ligand interactions and robustly increase survival of cancer patients but frequently result in immune-related adverse events (irAEs). While rheumatologic toxicities are commonly reported as irAEs, the effect of immune checkpoint blockade on the underlying mechanisms of ICI-induced fractures and bone loss is controversial, with reports of both positive and negative effects on bone mass in preclinical models. However, no previous reports have investigated the impact of ICIs on females or aged mice, or on fracture risk in either sex. We report that global deletion of programmed cell death protein 1 (PD-1) broadly results in bone loss in skeletally mature male and female PD-1-/- mice, with a sexually divergent phenotype in adolescent mice, decreased bone strength in adult males and young females, and expansion of multiple T cell subsets in the bone marrow. In a model of pharmacologic PD-1 blockade, administration of α-PD-1 reduced bone mass, expanded multiple T cell subsets in the bone marrow, and increased osteoclast activity and resorptive capacity. T cell deficient mice were resistant to osteoclast-mediated bone loss following α-PD-1 therapy, suggesting that T cells in the bone marrow are necessary for bone loss in the setting of ICI therapy. These findings may be leveraged to identify patients at greater fracture risk following ICI therapy due to enrichment of effector T cell populations in the bone marrow.
免疫检查点抑制剂（ICIs）可阻断免疫调节受体 - 配体相互作用，显著提高癌症患者的生存率，但常导致免疫相关不良事件（irAEs）。虽然风湿性毒性通常作为irAEs被报道，但免疫检查点阻断对ICI诱导的骨折和骨质流失潜在机制的影响存在争议，临床前模型中关于对骨量的正负影响均有报道。然而，此前尚无报告研究ICIs对雌性或老年小鼠的影响，或对任一性别人群骨折风险的影响。我们报告称，在骨骼成熟的雄性和雌性PD - 1基因敲除（PD - 1-/-）小鼠中，程序性细胞死亡蛋白1（PD - 1）的整体缺失广泛导致骨质流失，在青春期小鼠中存在性别差异表型，成年雄性和年轻雌性的骨强度降低，骨髓中多个T细胞亚群扩增。在药物性PD - 1阻断模型中，给予α - PD - 1可降低骨量，扩增骨髓中多个T细胞亚群，并增加破骨细胞活性和吸收能力。T细胞缺陷小鼠对α - PD - 1治疗后破骨细胞介导的骨质流失具有抗性，这表明在ICI治疗背景下，骨髓中的T细胞是骨质流失所必需的。这些发现可用于识别ICI治疗后骨折风险较高的患者，因为骨髓中效应T细胞群体增多。
