Abstract
Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems1-5. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)-one such nociceptor-produced neuropeptide-directly increases the exhaustion of cytotoxic CD8+ T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8+ T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8+ T cells, Ramp1-/- CD8+ T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8+ T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8+ T cells.
摘要
实体瘤受到来自自主神经和感觉周围神经系统的神经纤维的支配。痛觉神经元对肿瘤的新神经支配是否会影响癌症的免疫监视仍不清楚。在这项研究中，我们发现黑色素瘤细胞与痛觉神经元相互作用，导致它们的神经元突起、对有害配体的反应性和神经肽的释放增加。降钙素基因相关肽（CGRP）--一种由痛觉感受器产生的神经肽--直接增加了细胞毒性CD8+ T细胞的耗竭，从而限制了它们消灭黑色素瘤的能力。TRPV1系的基因消减、局部药物抑制痛觉感受器和拮抗CGRP受体RAMP1都能减少肿瘤浸润白细胞的耗竭，降低肿瘤的生长，使接种B16F10黑色素瘤细胞的小鼠存活率提高了近两倍。相反，用局部重组CGRP治疗的感觉神经元缺失小鼠的CD8+ T细胞衰竭得到了缓解。与野生型CD8+ T细胞相比，当Ramp1-/- CD8+ T细胞与Rag1基因缺陷小鼠共同移植到肿瘤小鼠体内时，Ramp1-/- CD8+ T细胞可防止衰竭。黑色素瘤患者活检组织的单细胞RNA测序显示，瘤内表达RAMP1的CD8+ T细胞比RAMP1阴性的CD8+ T细胞更容易衰竭，而RAMP1的过表达与较差的临床预后有关。总之，我们的研究结果表明，通过消除CGRP对细胞毒性CD8+ T细胞的免疫调节作用，减少肿瘤神经感受器释放CGRP可能是一种改善抗肿瘤免疫的策略。
参考文献
Balood M, Ahmadi M, Eichwald T, Ahmadi A, Majdoubi A, Roversi K, Roversi K, Lucido CT, Restaino AC, Huang S, Ji L, Huang KC, Semerena E, Thomas SC, Trevino AE, Merrison H, Parrin A, Doyle B, Vermeer DW, Spanos WC, Williamson CS, Seehus CR, Foster SL, Dai H, Shu CJ, Rangachari M, Thibodeau J, V Del Rincon S, Drapkin R, Rafei M, Ghasemlou N, Vermeer PD, Woolf CJ, Talbot S. Nociceptor neurons affect cancer immunosurveillance. Nature. 2022 Nov;611(7935):405-412. doi: 10.1038/s41586-022-05374-w.
