CCR2 silencing in sensory neurons blocks bone cancer progression

Abstract

The peripheral nervous system contributes to cancer growth, in part by shaping the immunological niche of the tumor. How the nervous system influences bone cancer progression, and whether the underlying neuroimmune pathways can be targeted therapeutically, remain unclear. Here we demonstrate a profound influence of the peripheral nervous system on tumor progression that can be countered by silencing chemokine receptor signaling in sensory neurons. Axotomy of the tumor-innervating femoral nerve inhibits tumor progression in animals bearing bone cancer, whereas intrathecal delivery of the tumor-associated proinflammatory chemokine CCL2 promotes both tumor growth and allodynia. Silencing CCR2 in dorsal root ganglion (DRG) neurons with a newly developed lipid nanoparticle-formulated Dicer-substrate siRNA impedes tumor progression and pathological bone remodeling, and relieves bone cancer-associated pain. Mechanistically, bone cancer drives CCR2-dependent transport of substance P and CGRP along the tumor-innervating femoral nerve, and these neuropeptides expand the tumor-associated macrophage population; silencing CCR2 in DRG neurons normalizes the neuropeptide milieu and ameliorates altered bone remodeling. We thus define a targetable neuroimmune axis that contributes to cancer progression. HighlightsO_LICancer progression activates sensory neurons, driving pain hypersensitivity and neuropeptide release. C_LIO_LIAxotomy of the tumor-innervating femoral nerve impedes tumor progression. C_LIO_LICCL2-CCR2 signaling in DRG neurons promotes pain hypersensitivity and cancer growth. C_LIO_LISilencing CCR2 in the DRG reduces pain hypersensitivity, tumor-associated macrophage numbers and cancer growth. C_LI