Nociceptor neurons affect cancer immunosurveillance.
Nociceptor neurons affect cancer immunosurveillance.
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DOI：
10.1038/s41586-022-05374-w
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发表时间：
2022-11
期刊：
影响因子：
64.8
通讯作者：
Talbot, Sebastien
中科院分区：
文献类型：
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作者：
Balood, Mohammad;Ahmadi, Maryam;Eichwald, Tuany;Ahmadi, Ali;Majdoubi, Abdelilah;Roversi, Karine;Roversi, Katiane;Lucido, Christopher T.;Restaino, Anthony C.;Huang, Siyi;Ji, Lexiang;Huang, Kai-Chih;Semerena, Elise;Thomas, Sini C.;Trevino, Alexandro E.;Merrison, Hannah;Parrin, Alexandre;Doyle, Benjamin;Vermeer, Daniel W.;Spanos, William C.;Williamson, Caitlin S.;Seehus, Corey R.;Foster, Simmie L.;Dai, Hongyue;Shu, Chengyi J.;Rangachari, Manu;Thibodeau, Jacques;Del Rincon, Sonia, V;Drapkin, Ronny;Rafei, Moutih;Ghasemlou, Nader;Vermeer, Paola D.;Woolf, Clifford J.;Talbot, Sebastien
实体瘤由来自自主和感觉周围神经系统的神经纤维支配。疼痛起始感觉神经元对肿瘤的新神经支配是否影响癌症免疫监视仍不清楚。在这里，我们表明，黑色素瘤细胞与伤害感受器神经元相互作用，导致其神经突生长，对有害配体和神经肽释放的反应增加。降钙素基因相关肽（CGRP）-一种伤害感受器产生的神经肽-直接增加细胞毒性CD 8 + T细胞的耗竭，这限制了它们消除黑色素瘤的能力。TRPV 1谱系的基因消融、伤害感受器的局部药理学沉默和CGRP受体RAMP 1的拮抗作用都减少了肿瘤浸润性白细胞的耗竭并降低了肿瘤的生长，使接种B16 F10黑色素瘤细胞的小鼠的存活率几乎增加了两倍。相反，在用局部重组CGRP治疗的感觉神经元耗竭小鼠中，CD 8 + T细胞耗竭被拯救。与野生型CD 8 + T细胞相比，当将Ramp 1 −/− CD 8 + T细胞共移植到携带肿瘤的Rag 1缺陷小鼠中时，可以保护其免于耗竭。黑色素瘤患者活检组织的单细胞RNA测序显示，肿瘤内RAMP 1表达的CD 8 + T细胞比RAMP 1阴性的T细胞消耗更多，而RAMP 1过表达与较差的临床预后相关。总体而言，我们的研究结果表明，减少CGRP从肿瘤神经支配的伤害感受器的释放可能是一种策略，通过消除CGRP对细胞毒性CD 8 + T细胞的免疫调节作用，以提高抗肿瘤免疫。黑色素瘤细胞通过增加神经肽CGRP的释放与疼痛介导的感觉神经元相互作用，这增加了CD 8 + T细胞的耗竭，从而促进癌细胞的存活。
Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems. 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. Melanoma cells interact with pain-mediating sensory neurons by increasing their release of the neuropeptide CGRP, which increases the exhaustion of CD8+ T cells and thus promotes the survival of cancer cells.
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影响因子：
11.2
作者：
Harlin H;Meng Y;Peterson AC;Zha Y;Tretiakova M;Slingluff C;McKee M;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
14.2
作者：
Crosson, Theo;Wang, Jo-Chiao;Doyle, Benjamin;Merrison, Hannah;Balood, Mohammad;Parrin, Alexandre;Pascal, Maud;Mindt, Barbara C.;Seehus, Corey R.;Ozcan, Alp;Huang, Xuan;Semenara, Elise;Lai, Nicole Y. Y.;Majdoubi, Abdelilah;Abdulnour, Raja-Elie E.;Rajchgot, Trevor;Rafei, Moutih;Foster, Simmie L.;Thibodeau, Jacques;Fritz, Joerg H.;Levy, Bruce D.;Woolf, Clifford J.;Talbot, Sebastien
通讯作者：
Talbot, Sebastien
DOI：
10.1016/j.jpain.2014.09.010
发表时间：
2014-12
期刊：
The journal of pain
影响因子：
--
作者：
Goswami SC;Mishra SK;Maric D;Kaszas K;Gonnella GL;Clokie SJ;Kominsky HD;Gross JR;Keller JM;Mannes AJ;Hoon MA;Iadarola MJ
通讯作者：
Iadarola MJ
DOI：
10.4049/jimmunol.181.9.6020
发表时间：
2008-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ding W;Stohl LL;Wagner JA;Granstein RD
通讯作者：
Granstein RD
影响因子：
64.8
作者：
通讯作者：
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