Treatment of non-small cell lung cancer (NSCLC) has drastically changed in recent years owing to the robust anti-cancer effects of immune-checkpoint inhibitors (ICI). However, only 20% of NSCLC patients benefit from ICIs, highlighting the need to uncover the mechanisms mediating resistance. By analyzing the overall survival (OS) and mutational profiles of 424 NSCLC patients who received ICI treatments between 2015 and 2021, we determined that patients carrying a loss of function mutation in neurotrophic tyrosine kinase receptor 1 (NTRK1) had a prolonged OS compared to patients with wild-type NTRK1. Notably, suppression of the NTRK1 pathway by knockdown or Entrectinib treatment significantly enhanced ICI efficacy in mouse NSCLC models. Comprehensive T cell population analyses demonstrated that stem-like CD4+ T cells and effector CD4+ and CD8+ T cells were highly enriched in anti-PD-1 treated mice bearing tumors with decreased NTRK1 signaling. RNA sequencing revealed that suppression of NTRK1 signaling in tumor cells increased complement C3 expression, which enhanced the recruitment of T cells and myeloid cells and stimulated M1-like macrophage polarization in the tumor. Together, this study demonstrates a role for NTRK1 signaling in regulating crosstalk between tumor cells and immune cells in the tumor microenvironment and provides a potential therapeutic approach to overcomes immunotherapy resistance in NTRK1 wild-type NSCLC patients.

中文翻译：

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靶向 NTRK1 增强 NTRK1 野生型非小细胞肺癌免疫检查点抑制剂疗效


由于免疫检查点抑制剂 （ICI） 强大的抗癌作用，近年来非小细胞肺癌 （NSCLC） 的治疗发生了巨大变化。然而，只有 20% 的 NSCLC 患者受益于 ICIs，这凸显了揭示介导耐药机制的必要性。通过分析 2015 年至 2021 年间接受 ICI 治疗的 424 例 NSCLC 患者的总生存期 （OS） 和突变谱，我们确定携带神经营养性酪氨酸激酶受体 1 （NTRK1） 功能丧失突变的患者与野生型 NTRK1 患者相比，OS 延长。值得注意的是，通过敲低或 Entrectinib 治疗抑制 NTRK1 通路显着增强了小鼠 NSCLC 模型中的 ICI 疗效。全面的 T 细胞群分析表明，干细胞样 CD4 + T 细胞和效应 CD4 + 和 CD8 + T 细胞在携带 NTRK1 信号传导降低的肿瘤的抗 PD-1 处理小鼠中高度富集。RNA 测序显示，肿瘤细胞中 NTRK1 信号的抑制增加了补体 C3 的表达，从而增强了 T 细胞和骨髓细胞的募集，并刺激了肿瘤中 M1 样巨噬细胞极化。总之，本研究证明了 NTRK1 信号转导在调节肿瘤微环境中肿瘤细胞和免疫细胞之间的串扰中的作用，并为克服 NTRK1 野生型 NSCLC 患者的免疫治疗耐药提供了一种潜在的治疗方法。