Abstract
Patients with advanced stage cancers frequently suffer from severe pain as a result of bone metastasis and bone destruction, for which there is no efficacious treatment. Here, using multiple mouse models of bone cancer, we report that agonists of the immune regulator STING (stimulator of interferon genes) confer remarkable protection against cancer pain, bone destruction, and local tumor burden. Repeated systemic administration of STING agonists robustly attenuates bone cancer-induced pain and improves locomotor function. Interestingly, STING agonists produce acute pain relief through direct neuronal modulation. Additionally, STING agonists protect against local bone destruction and reduce local tumor burden through modulation of osteoclast and immune cell function in the tumor microenvironment, providing long-term cancer pain relief. Finally, these in vivo effects are dependent on host-intrinsic STING and IFN-I signaling. Overall, STING activation provides unique advantages in controlling bone cancer pain through distinct and synergistic actions on nociceptors, immune cells, and osteoclasts.
Highlights
Patients with advanced stage cancers frequently suffer from severe pain as a result of bone metastasis and bone destruction, for which there is no efficacious treatment
Similar to our results in the LLC bone cancer pain model, we found that DMXAA and ADU-S100 treatment could markedly reduce mechanical allodynia, cold allodynia and spontaneous pain compared to vehicle treatment (Supplementary Fig. 3b–d) but had no effect on body weight (Supplementary Fig. 3e)
Given our previous report in which we demonstrated that STING agonists can directly suppress nociceptor hyperexcitability in a chemotherapy-induced peripheral neuropathy (CIPN) model of chronic pain[23], we posited that STING agonists may acutely attenuate bone cancer-induced hyperexcitability of peripheral nociceptors, To test this hypothesis, WT mice were inoculated with LLC cells to establish bone cancer models and lumbar L3–L5 dorsal root ganglion (DRG) were isolated on d11 and incubated ex vivo with vehicle or DMXAA (30 μM) for 2 h followed by patch clamp recordings to measure nociceptor excitability (Fig. 4a)
Summary
Patients with advanced stage cancers frequently suffer from severe pain as a result of bone metastasis and bone destruction, for which there is no efficacious treatment. STING agonists protect against local bone destruction and reduce local tumor burden through modulation of osteoclast and immune cell function in the tumor microenvironment, providing long-term cancer pain relief These in vivo effects are dependent on host-intrinsic STING and IFN-I signaling. It is generally believed that activation of pain-sensing nociceptive neurons (nociceptors) by soluble mediators released from cancer cells and osteoclasts drives bone cancer pain Based on these studies, and taken in conjunction with the promise STING agonists have shown as cancer immunotherapy agents, we posited that activation of the STING pathway in bone cancer may be a unique synergistic approach to concurrently promote antitumor immunity, suppress bone destruction, and provide pain control. In this study we demonstrate that small molecule agonists of STING provide long-lasting relief from cancer-induced bone pain via distinct and synergistic actions on pain-sensing nociceptors, adaptive immune cells, and osteoclasts through a mechanism dependent on IFN-I signaling
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