GSE193065
Sensory nerves in melanoma impede the formation of tertiary lymphoid structures and anti-tumor immune responses
Utilizing surgical and chemical skin sensory denervation methods, we show that afferent neurons support the growth of melanoma tumors in vivo. We demonstrate that sensory innervation limits the activation of effective anti-tumor immune response. Specifically, sensory ablation led to improved leukocyte recruitment and infiltration into tumors, decreased intratumoral lymphoid and myeloid immunosuppressive cells, and the activation of T effector cells within the TME. We found that cutaneous sensory nerves hinder the maturation of intratumoral high endothelial venules and the formation of mature tertriary 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 the denervation-dependent anti-tumor effects. Finally, we observed that the gene signatures associated with immune function and sensory innervation were inversely correlated in human primary cutaneous melanomas, and the latter was a negative prognostic marker of the overall survival in the examined cohort. Our results suggest that tumor-associated sensory neurons negatively regulate the development of effective anti-tumor immune responses, thereby defining a novel target for therapeutic intervention in the cancer setting. Overall design: mRNA profiles of innervated versus denervated B16F10 tumors established in C57Bl/6 mice.