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 7

Bone cancer is associated with increased PD-1 expression in tumor-bearing femora.

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Bone cancer is associated with increased PD-1 expression in tumor-bearin...
(A) Immunostaining images showing PD-1 expression in ipsilateral BM and contralateral BM on 8 days after inoculation. Scale bar: 1000 μm. Note the sample of contralateral BM here is the same as the contralateral BM shown in Figure 6F. Low-magnification images on the left and right are enlarged in middle boxes showing PD-1 staining in normal BM environment and in tumor microenvironment. Scale bars: 200 μm (contralateral BM); 100 μm (ipsilateral BM). (B) Double staining of PD-L1 (red) and PD-1 (white) in ipsilateral BM on day 8. The boxes in the left panels are enlarged in the right panels. Scale bars: 100 μm. (C and D) Increased expression of PD-1 in monocytes (C) and microphages (D) in ipsilateral BM inoculated with tumor compared with contralateral BM and BM of naive mice. Monocytes were labeled as CD3–, CD45+, and CD14+ cells, and macrophages were identified as F4/80+ cells. Top: representative images of flow cytometry. Bottom: quantification of percentages of PD-1+ cells in monocyte and macrophage populations. n = 3–6 mice. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01, 1-way ANOVA with Bonferroni’s post hoc test.