Nociceptor Neurons Affect Immunosurveillance and Tumor Growth

Neoinnervation has been shown to occur in multiple tumor types, while released neuropeptides have been demonstrated to affect immune cells. However, the effects of neoinnervation and neuropeptides specifically on cancer immunosurveillance have not yet been demonstrated. Balood, Ahmadi, and colleagues sought to examine how release of neuropeptides from activated pain-initiating sensory (nociceptor) neurons can alter tumor growth through immune surveillance and showed that melanomas are innervated by TRPV1⁺ nociceptor neurons, with the number of tumor-infiltrating lymphocytes correlating with this increase in nociceptor neurons. Sensitivity of these nociceptor neurons was increased when in close physical proximity to melanoma cells, leading to release of the immunomodulatory neuropeptide calcitonin gene–related peptide (CGRP). Evaluation of nociceptor effects on tumor control revealed a reduction in tumor growth as well as an increase in tumor-infiltrating CD8⁺ T cells when nociceptor neurons were ablated. Additionally, nociceptor neuron stimulation increased the proportion of PD-1⁺ LAG3⁺ TIM3⁺–expressing CD8⁺ T cells while decreasing the proportion of IFNγ⁺, TNF⁺, IL2⁺ CD8⁺ T cells, suggesting that these nociceptor neurons promote T-cell exhaustion. Tumor-innervating nociceptor neurons were also able to affect responsiveness of anti–PD-L1 treatment in a murine melanoma tumor model. Mechanistically, CGRP release by nociceptor neurons was able to bind to RAMP1 on the surface of CD8⁺ T cells, with mice treated with a RAMP1 antagonist demonstrating reduced melanoma tumor growth and exhausted T-cell frequency. Moreover, Rag1^−/− mice transplanted with Ramp1^−/− CD8⁺ T cells were CGRP unresponsive, which protected them from nociceptor neuron–induced T-cell exhaustion and retained their antitumor responses. Furthermore, samples from human patients with melanoma revealed that CD8⁺ T cells overexpressing RAMP1 correlated with reduced survival; increased immune checkpoint receptor expression, including PD-1; and heightened resistance to immune checkpoint inhibitors. Overall, these results show that the presence of nociceptor neurons increases tumor growth by inducing CD8⁺ T-cell exhaustion, suggesting that targeting procancerous neuroimmune networks could lead to improved cancer immunotherapies.

Balood M, Ahmadi M, Eichwald T, Ahmadi A, Majdoubi A, Roversi K, et al. Nociceptor neurons affect cancer immunosurveillance. Nature 2022;611:405–12.

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