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

K Wang, Y Gu, Y Liao, S Bang… - The Journal of …, 2020 - Am Soc Clin Investig
The Journal of clinical investigation, 2020Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation