PD-1 blockade inhibits osteoclast formation and murine bone cancer pain
Kaiyuan Wang, … , Matthew J. Hilton, Ru-Rong Ji
Kaiyuan Wang, … , Matthew J. Hilton, Ru-Rong Ji
Published June 2, 2020
Citation Information: J Clin Invest. 2020;130(7):3603-3620. https://doi.org/10.1172/JCI133334.
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Research Article Cell biology Neuroscience

PD-1 blockade inhibits osteoclast formation and murine bone cancer pain

Abstract

Emerging immune therapy, such as with the anti–programmed cell death–1 (anti–PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 (Pd1−/−) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, Pd1−/− mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in Pd1−/− mice. Consistently, these beneficial effects in Pd1−/− mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti–PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis.

Authors

Kaiyuan Wang, Yun Gu, Yihan Liao, Sangsu Bang, Christopher R. Donnelly, Ouyang Chen, Xueshu Tao, Anthony J. Mirando, Matthew J. Hilton, Ru-Rong Ji

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Figure 5

Effects of nivolumab or Pd1 deletion on TRAP+ osteoclasts and ALP + osteoblasts in tumor-bearing femur.

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Effects of nivolumab or Pd1 deletion on TRAP+ osteoclasts and ALP + oste...
(A) Histological images of TRAP staining of osteoclasts in femurs from mice treated with human IgG or nivolumab (10 mg/kg, i.v.). Scale bar: 500 μm. (B) Quantification of TRAP staining in distal tumor-bearing femora (4–10 slices per femur, n = 5–6 male mice). (C) Histological images for ALP staining of osteoblasts of femur bones from human IgG– or nivolumab-treated mice. Scale bar: 500 μm. (D) Quantification of ALP staining of osteoblasts in distal femora (4–10 sections per femur, n = 5 male mice per group). (E and F) Representative images (E) and quantification of TRAP staining (F) in Pd1−/− mice and WT mice on postinoculation day 8 (4–10 slices per femur, n = 5 male mice). Scale bar: 500 μm. (G and H) Representative images (G) and quantification of ALP staining (H) showing osteoblasts in Pd1−/− mice and WT mice on postinoculation day 8 (4–10 slices per femur, n = 5 male mice). Scale bar: 500 μm. (I and J) ELISA analysis showing the effects of nivolumab and IgG on serum levels of CTX-I (I) and PINP (J) on postinoculation day. n = 6–7 male mice. Data are represented as mean ± SEM. *P < 0.05; ***P < 0.001, 2-tailed Student’s t test (B, D, F, and H) and repeated measures 2-way ANOVA with Bonferroni’s post hoc test (I and J). Oc.S/BS, osteoclast surface per trabecular bone surface; Ob.N/BS, osteoblast number per trabecular bone surface.