Restaino Anthony C, Ahmadi Maryam, Eichwald Tuany, Nikpoor Amin Reza, Walz Austin, Balood Mohammad, Talbot Sebastien, Vermeer Paola D
Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD 57104, USA.
Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57104, USA.
Sci Signal. 2025 Aug 5;18(898):eads7889. doi: 10.1126/scisignal.ads7889.
Small extracellular vesicles (sEVs) released from tumors recruit nociceptor neurons to the tumor bed. Here, we found that ablating these neurons in mouse models of head and neck carcinoma and melanoma reduced the infiltration of myeloid-derived suppressor cells (MDSCs). Moreover, sEV-deficient tumors failed to develop in mice lacking nociceptor neurons. We investigated the interplay between tumor-infiltrating nociceptors and immune cells in head and neck squamous cell carcinoma (HNSCC) and melanoma. Upon exposure to cancer-derived sEVs, mouse dorsal root ganglion (DRG) neurons secreted increased amounts of substance P, IL-6, and injury-associated neuronal markers. Patient-derived sEVs sensitized DRG neurons to capsaicin, implying enhanced nociceptor responsiveness. Furthermore, nociceptors cultured with sEVs induced an immunosuppressed state in CD8 T cells. Incubation with conditioned medium from cocultures of neurons and cancer cells resulted in increased expression of markers of MDSCs and suppressive function in primary bone marrow cells, and the combination of neuron-conditioned medium and cancer sEVs promoted checkpoint receptor expression on T cells. Together, these findings reveal that nociceptor neurons facilitate CD8 T cell exhaustion and bolster MDSC infiltration into HNSCC and melanoma. Consequently, targeting nociceptors may provide a strategy to disrupt detrimental neuroimmune cross-talk in cancer and potentiate antitumor immunity.
肿瘤释放的小细胞外囊泡（sEVs）将伤害感受神经元募集到肿瘤床。在此，我们发现，在头颈癌和黑色素瘤小鼠模型中消融这些神经元可减少髓源性抑制细胞（MDSC）的浸润。此外，缺乏sEV的肿瘤在缺乏伤害感受神经元的小鼠中无法生长。我们研究了头颈鳞状细胞癌（HNSCC）和黑色素瘤中肿瘤浸润性伤害感受器与免疫细胞之间的相互作用。暴露于癌症衍生的sEVs后，小鼠背根神经节（DRG）神经元分泌的P物质、白细胞介素-6和损伤相关神经元标志物的量增加。患者来源的sEVs使DRG神经元对辣椒素敏感，这意味着伤害感受器反应性增强。此外，与sEVs共培养的伤害感受器在CD8 T细胞中诱导了免疫抑制状态。用神经元和癌细胞共培养的条件培养基孵育导致原代骨髓细胞中MDSC标志物的表达增加和抑制功能增强，并且神经元条件培养基和癌症sEVs的组合促进了T细胞上检查点受体的表达。总之，这些发现表明伤害感受神经元促进CD8 T细胞耗竭，并增强MDSC向HNSCC和黑色素瘤中的浸润。因此，靶向伤害感受器可能提供一种策略，以破坏癌症中有害的神经免疫串扰并增强抗肿瘤免疫力。
