Monocyte reprogramming by nociceptors impedes T cell-mediated tumor immunity

Nociceptors - peripheral nervous system neurons that trigger the sensation of pain or itch in response to noxious stimuli - can communicate with leukocytes and modulate immune responses in a context-dependent manner1,2. Here, we demonstrate that nociceptors rapidly induce monocytes to adopt an immunosuppressive phenotype, reminiscent of myeloid-derived suppressor cells (MDSCs), which have been linked to impaired anti-tumor immunity. MDSCs are abundant in human bladder cancer, a malignancy where survival is negatively correlated with expression of pro-neurogenic cytokines. Accordingly, in an orthotopic mouse model of urinary bladder carcinoma, incipient tumors promoted dense innervation by nociceptors and infiltration by monocytes that differentiated rapidly into MDSCs. Nociceptors did not affect the development of tumor-specific T cells in draining lymph nodes, but they were essential during the early stages of tumor formation to establish an immunosuppressive tumor microenvironment. Ablation or chemogenetic inhibition of nociceptors prevented the formation of immunosuppressive MDSCs and markedly increased the rate of bladder tumor rejection by T cells. Conversely, monocyte depletion in nociceptor-sufficient mice enabled tumor rejection. Collectively, these findings demonstrate that urothelial tumors co-opt an immunosuppressive neuro-immune axis to evade anti-tumor immunity and identify nociceptors as potential targets for bladder cancer treatment.