Nerve Growth Factor (NGF) drives ILC2 pro-tumoral functions - bulk RNA sequencing of human TRKA+ and TRKA- ILC2s

ILC2s are key regulators of tissue homeostasis and inflammation. In cancer, ILC2s can exhibit pro-tumoral functions by increasing the MDSC/T-cell ratio. Nevertheless, the upstream ILC2 triggers remain poorly defined. Here, we identify NGF as the driver of ILC2 pro-tumoral functions in bladder cancer patients. We show that ILC2s express the NGF receptor TrkA and respond to NGF by secreting type-2 cytokines. In the tumor microenvironment, NGF-producing mast cells accumulate and activate ILC2s to induce Tregs, ultimately fostering tumor growth. In patients, NGF levels inversely correlate with survival in ILC2-rich tumors, underscoring the clinical significance of this axis. In vivo administration of a selective TrkA inhibitor improves survival in orthotopic tumor-bearing animals and sensitizes them to immune checkpoint blockade (ICB). Overall, we identify NGF as a novel ILC2 activator that shapes pro-tumoral ILC2 functions. The blockade of TrkA+ ILC2s might represent a targetable strategy to improve survival, particularly in ICB-resistant patients. Overall design: To uncover transcriptomic differences between TrkA+ and TrkA- ILC2s, we sorted these two subpopulations from PBMCs of three healthy donors and performed bulk RNAseq.

固有淋巴细胞2型（Innate Lymphoid Cells Type 2, ILC2s）是组织稳态与炎症的关键调节因子。在癌症中，ILC2s可通过升高髓系来源抑制细胞（Myeloid-Derived Suppressor Cells, MDSC）/T细胞比值，发挥促肿瘤功能。然而，ILC2激活的上游触发因素仍未得到明确阐释。本研究证实，神经生长因子（Nerve Growth Factor, NGF）是膀胱癌患者体内ILC2s发挥促肿瘤功能的驱动因子。研究发现，ILC2s表达NGF受体原肌球蛋白受体激酶A（Tropomyosin Receptor Kinase A, TrkA），并可通过分泌2型细胞因子对NGF产生应答。在肿瘤微环境中，分泌NGF的肥大细胞会聚集并激活ILC2s，进而诱导调节性T细胞（Regulatory T Cells, Tregs）生成，最终促进肿瘤生长。在患者群体中，ILC2富集型肿瘤内的NGF水平与患者生存期呈负相关，凸显了该信号轴的临床意义。体内给予选择性TrkA抑制剂可延长原位荷瘤动物的生存期，并可使其对免疫检查点阻断（Immune Checkpoint Blockade, ICB）治疗产生增敏效果。综上，本研究证实NGF是一种全新的ILC2激活因子，可调控ILC2s的促肿瘤功能。靶向阻断TrkA阳性ILC2s或许可作为改善患者生存期的可干预策略，尤其适用于免疫检查点阻断治疗耐药的患者。实验整体设计：为解析TrkA阳性与TrkA阴性ILC2s之间的转录组差异，我们从3名健康志愿者的外周血单个核细胞（Peripheral Blood Mononuclear Cells, PBMCs）中分离得到这两个亚群，并开展了批量RNA测序（bulk RNA sequencing, bulk RNAseq）。