Sensory nerves impede the formation of tertiary lymphoid structures and development of protective anti-melanoma immune responses

Peripheral neurons comprise a critical component of the tumor microenvironment (TME). The role of the autonomic innervation in cancer has been firmly established. However, the effect of the afferent (sensory) neurons on tumor progression remains unclear. Utilizing surgical and chemical skin sensory denervation methods, we showed that afferent neurons supported the growth of melanoma tumors in vivo and demonstrated that sensory innervation limited the activation of effective anti-tumor immune responses. Specifically, sensory ablation led to improved leukocyte recruitment into tumors, with decreased presence of lymphoid and myeloid immunosuppressive cells and increased activation of T-effector cells within the TME. Cutaneous sensory nerves hindered maturation of intratumoral high endothelial venules (HEVs) and limited formation of mature tertiary lymphoid-like structures containing organized clusters of CD4 + T cells and B cells. Denervation further increased T-cell clonality and expanded the B-cell repertoire in the TME. Importantly, CD8a depletion prevented denervation-dependent anti-tumor effects. Finally, we observed that gene signatures of inflammation and the content of neuron-associated transcripts inversely correlated in human primary cutaneous melanomas, with the latter representing a negative prognostic marker of patient overall survival. Our results suggest that tumor-associated sensory neurons negatively regulate the development of protective anti-tumor immune responses within the TME, thereby defining a novel target for therapeutic intervention in the melanoma setting. Sensory neurons are shown to play a critical role in the modulation of anti-tumor immune responses and the formation of tertiary lymphoid structures in melanoma. Data highlight afferent innervation as a potential novel target for cancer immunotherapy.