美国杜克大学Qi-Jing Li等研究人员合作发现，破坏黑色素瘤中的NGF-TrkA免疫抑制使得免疫疗法对持久的记忆T细胞保护敏感。相关论文于2024年1月9日在线发表在《自然—免疫学》杂志上。

研究人员发现神经生长因子（NGF）具有黑色素瘤细胞内在和外在免疫抑制功能。自分泌的NGF与黑色素瘤细胞上的肌球蛋白受体激酶 A（TrkA）结合，使干扰素γ信号脱敏，导致T细胞和自然杀伤细胞被排斥。效应T细胞在T细胞受体激活时会上调表面TrkA的表达，旁分泌型NGF会抑制T细胞受体信号传导和效应细胞功能。通过基因修饰或使用肌球蛋白受体激酶抑制剂拉罗替尼抑制NGF，可使黑色素瘤易受免疫检查点阻断疗法的影响，并通过激活低亲和力的记忆T细胞促进长期免疫。

这些结果确定了NGF-TrkA轴是抗肿瘤免疫的重要抑制因子，并表明拉罗替尼可能被重新用于免疫增敏。此外，通过招募低亲和力T细胞，抗NGF可降低对免疫检查点阻断的获得性抵抗，从而防止黑色素瘤复发。

研究人员表示，黑色素瘤细胞来源于神经外胚层黑色素细胞，可能会利用神经系统的免疫豁免生长。

附：英文原文

Title: Breaking NGF–TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection

Author: Yin, Tao, Wang, Guoping, Wang, Liuyang, Mudgal, Poorva, Wang, Ergang, Pan, Christopher C., Alexander, Peter B., Wu, Haiyang, Cao, Chengjie, Liang, Yaosi, Tan, Lianmei, Huang, De, Chong, Mengyang, Chen, Rui, Lim, Bryan Jian Wei, Xiang, Kun, Xue, Wei, Wan, Lixin, Hu, Hailan, Loh, Yuin-Han, Wang, Xiao-Fan, Li, Qi-Jing

Issue&Volume: 2024-01-09

Abstract: Melanoma cells, deriving from neuroectodermal melanocytes, may exploit the nervous system’s immune privilege for growth. Here we show that nerve growth factor (NGF) has both melanoma cell intrinsic and extrinsic immunosuppressive functions. Autocrine NGF engages tropomyosin receptor kinase A (TrkA) on melanoma cells to desensitize interferon γ signaling, leading to T and natural killer cell exclusion. In effector T cells that upregulate surface TrkA expression upon T cell receptor activation, paracrine NGF dampens T cell receptor signaling and effector function. Inhibiting NGF, either through genetic modification or with the tropomyosin receptor kinase inhibitor larotrectinib, renders melanomas susceptible to immune checkpoint blockade therapy and fosters long-term immunity by activating memory T cells with low affinity. These results identify the NGF–TrkA axis as an important suppressor of anti-tumor immunity and suggest larotrectinib might be repurposed for immune sensitization. Moreover, by enlisting low-affinity T cells, anti-NGF reduces acquired resistance to immune checkpoint blockade and prevents melanoma recurrence.

DOI: 10.1038/s41590-023-01723-7

Source: https://www.nature.com/articles/s41590-023-01723-7