CCR2-targeting pepducins reduce T cell-nociceptor interaction driving bone cancer pain

Abstract

AbstractInhibition of the CCL2/CCR2 chemokine signaling represents a promising avenue for the development of non-opioid pain treatment, particularly for painful bone metastases. To investigate the involvement of CCR2 in cancer-induced bone pain, we generated and characterized the functional activities of a novel cell-penetrating pepducin, namely PP101, acting as an intracellular negative allosteric modulator of CCR2.In vivo, PP101 was effective in relieving neuropathic and bone cancer pain. By targeting CCR2, PP101 reduced bone cancer pain by preventing infiltration of CD4+and CD8+T cells and by decreasing the neuroimmune communication network within the dorsal root ganglia. Importantly, reduced neuroinflammatory milieu in the dorsal root ganglia induced by PP101 did not result in deleterious tumor progression or behavioral adverse effects. Thus, targeting the neuroimmune crosstalk through allosteric inhibition of CCR2 may represent an effective and safe avenue for the management of bone cancer pain.Graphical AbstractHighlightsBreast cancer bone metastases induce pain by activating CCR2 on sensory neurons.DRG-infiltrating CD4+and CD8+T cells promote the development of bone cancer pain.CCR2 inhibition by PP101 suppresses DRG neuroinflammation and neuronal excitability.PP101 alleviates bone cancer pain without behavioral or physiological side effects.