PDF(Pubmed)
Abstract：
BACKGROUND: Skeletal morbidity in patients with cancer has a major impact on the quality of life, and preserving bone health while improving outcomes is an important goal of modern antitumor treatment strategies. Despite their widespread use in early disease stages, the effects of immune checkpoint inhibitors (ICIs) on the skeleton are still poorly defined. Here, we initiated a comprehensive investigation of the impact of ICIs on bone health by longitudinal assessment of bone turnover markers in patients with cancer and by validation in a novel bioengineered 3D model of bone remodeling.
METHODS: An exploratory longitudinal study was conducted to assess serum markers of bone resorption (C-terminal telopeptide, CTX) and formation (procollagen type I N-terminal propeptide, PINP, and osteocalcin, OCN) before each ICI application (programmed cell death 1 (PD1) inhibitor or programmed death-ligand 1 (PD-L1) inhibitor) for 6 months or until disease progression in patients with advanced cancer and no evidence of bone metastases. To validate the in vivo results, we evaluated osteoclast (OC) and osteoblast (OB) differentiation on treatment with ICIs. In addition, their effect on bone remodeling was assessed by immunohistochemistry, confocal microscopy, and proteomics analysis in a dynamic 3D bone model.
RESULTS: During the first month of treatment, CTX levels decreased sharply but transiently. In contrast, we observed a delayed increase of serum levels of PINP and OCN after 4 months of therapy. In vitro, ICIs impaired the maturation of preosteoclasts by inhibiting STAT3/NFATc1 signaling but not JNK, ERK, and AKT while lacking any direct effect on osteogenesis. However, using our bioengineered 3D bone model, which enables the simultaneous differentiation of OB and OC precursor cells, we confirmed the uncoupling of the OC/OB activity on exposure to ICIs by demonstrating impaired OC maturation along with increased OB differentiation.
CONCLUSIONS: Our study indicates that the inhibition of the PD1/PD-L1 signaling axis interferes with bone turnover and may exert a protective effect on bone by indirectly promoting osteogenesis.
METHODS: An exploratory longitudinal study was conducted to assess serum markers of bone resorption (C-terminal telopeptide, CTX) and formation (procollagen type I N-terminal propeptide, PINP, and osteocalcin, OCN) before each ICI application (programmed cell death 1 (PD1) inhibitor or programmed death-ligand 1 (PD-L1) inhibitor) for 6 months or until disease progression in patients with advanced cancer and no evidence of bone metastases. To validate the in vivo results, we evaluated osteoclast (OC) and osteoblast (OB) differentiation on treatment with ICIs. In addition, their effect on bone remodeling was assessed by immunohistochemistry, confocal microscopy, and proteomics analysis in a dynamic 3D bone model.
RESULTS: During the first month of treatment, CTX levels decreased sharply but transiently. In contrast, we observed a delayed increase of serum levels of PINP and OCN after 4 months of therapy. In vitro, ICIs impaired the maturation of preosteoclasts by inhibiting STAT3/NFATc1 signaling but not JNK, ERK, and AKT while lacking any direct effect on osteogenesis. However, using our bioengineered 3D bone model, which enables the simultaneous differentiation of OB and OC precursor cells, we confirmed the uncoupling of the OC/OB activity on exposure to ICIs by demonstrating impaired OC maturation along with increased OB differentiation.
CONCLUSIONS: Our study indicates that the inhibition of the PD1/PD-L1 signaling axis interferes with bone turnover and may exert a protective effect on bone by indirectly promoting osteogenesis.
摘要：
背景：癌症患者的骨骼发病率对生活质量有重大影响，保持骨骼健康，同时改善预后是现代抗肿瘤治疗策略的重要目标。尽管它们在疾病早期阶段广泛使用，免疫检查点抑制剂(ICIs)对骨骼的影响尚不明确.这里,我们通过对癌症患者骨转换标志物的纵向评估以及在新型生物工程骨重塑3D模型中的验证,启动了ICI对骨健康影响的全面研究.
方法：进行了一项探索性纵向研究，以评估骨吸收的血清标志物（C末端端肽，CTX）和形成（I型前胶原N端前肽，PINP,和骨钙蛋白，OCN）在每次ICI应用之前（程序性细胞死亡1（PD1）抑制剂或程序性死亡配体1（PD-L1）抑制剂）持续6个月或直到晚期癌症患者的疾病进展并且没有骨转移的证据。为了验证体内结果，我们评估了ICIs治疗后的破骨细胞（OC）和成骨细胞（OB）分化。此外,它们对骨重建的影响通过免疫组织化学评估，共聚焦显微镜，和动态三维骨模型中的蛋白质组学分析。
结果：在治疗的第一个月，CTX水平急剧下降，但短暂下降。相比之下,我们观察到治疗4个月后血清PINP和OCN水平延迟升高.体外，ICIs通过抑制STAT3/NFATc1信号而不是JNK来损害破骨细胞的成熟，ERK,和AKT，但对成骨没有任何直接作用。然而,使用我们的生物工程3D骨骼模型，能够同时分化OB和OC前体细胞，通过证明OC成熟受损以及OB分化增加，我们证实了OC/OB活性在暴露于ICIs时的解偶联。
结论：我们的研究表明，PD1/PD-L1信号轴的抑制干扰了骨转换，并可能通过间接促进骨生成而对骨产生保护作用。
方法：进行了一项探索性纵向研究，以评估骨吸收的血清标志物（C末端端肽，CTX）和形成（I型前胶原N端前肽，PINP,和骨钙蛋白，OCN）在每次ICI应用之前（程序性细胞死亡1（PD1）抑制剂或程序性死亡配体1（PD-L1）抑制剂）持续6个月或直到晚期癌症患者的疾病进展并且没有骨转移的证据。为了验证体内结果，我们评估了ICIs治疗后的破骨细胞（OC）和成骨细胞（OB）分化。此外,它们对骨重建的影响通过免疫组织化学评估，共聚焦显微镜，和动态三维骨模型中的蛋白质组学分析。
结果：在治疗的第一个月，CTX水平急剧下降，但短暂下降。相比之下,我们观察到治疗4个月后血清PINP和OCN水平延迟升高.体外，ICIs通过抑制STAT3/NFATc1信号而不是JNK来损害破骨细胞的成熟，ERK,和AKT，但对成骨没有任何直接作用。然而,使用我们的生物工程3D骨骼模型，能够同时分化OB和OC前体细胞，通过证明OC成熟受损以及OB分化增加，我们证实了OC/OB活性在暴露于ICIs时的解偶联。
结论：我们的研究表明，PD1/PD-L1信号轴的抑制干扰了骨转换，并可能通过间接促进骨生成而对骨产生保护作用。
