Tumor-innervating nociceptors drive immuno-suppressive monocyte differentiation to prevent T cell-mediated anti-cancer immunity 2259756

Abstract

Abstract Introduction 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 manner. Indeed, recent work has indicated that nociceptors may also play important roles in tumor immunity. Nevertheless, much remains unknown about which types of tumors may be affected by nociceptors and what the effects of nociceptors are. Results Here, using The Cancer Genome Atlas (TCGA), we found that in human patients with urinary bladder carcinoma (BC), high expression of neurotrophic factors promoting sensory innervation correlated with significantly worse prognosis. Accordingly, in a murine orthotopic model of BC, incipient tumors promoted dense innervation by nociceptors. Strikingly, nociceptor ablation significantly decreased tumor incidence in WT but not RAG-deficient animals, indicating that nociceptors may prevent immune-mediated eradication of tumors. Nevertheless, nociceptors did not directly affect the development of tumor antigen-specific T cells in tumor-draining lymph nodes; rather, their activity was essential during the early stages of tumor formation to establish an immunosuppressive microenvironment, which protected the tumor cells from T-lymphocyte-mediated killing. As a result, chemogenetic inhibition of nociceptors during the early stages of tumorigenesis markedly increased the rate of BC rejection. Mechanistically, we observed that nociceptors induce a phenotype reminiscent of myeloid-derived suppressor cells (MDSC) in tumor-infiltrating monocytes, imbuing them with the ability to inhibit T-cell responses. Accordingly, monocyte depletion in nociceptor-sufficient mice also inhibited BC formation. Conclusion Collectively, these findings demonstrate that solid tumors can co-opt an immunosuppressive neuro-immune axis to evade anti-tumor immunity, and identify nociceptors as potential targets for bladder cancer treatment. Funding Source n/a Topic Categories Neuroimmunology (NEUR)